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Wu Z, Li Y, Dong J, Qin JJ. An updated review on the role of small molecules in mediating protein degradation. Eur J Med Chem 2025; 287:117370. [PMID: 39933402 DOI: 10.1016/j.ejmech.2025.117370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/25/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Targeted protein degradation (TPD) technologies, inspired by physiological processes, have recently provided new directions for drug development. Unlike conventional drug development focusing on targeting the active sites of disease-related proteins, TPD can utilize any nook or cranny of a protein to drive degradation through the cell's inherent destruction mechanism. It offers various advantages such as stronger pharmacological effects, an expanded range of drug targets, and higher selectivity. Based on the ubiquitin-proteasome system and the lysosomal degradation pathway, a variety of TPD strategies have been developed including PROTAC, PROTAB, and AUTOTAC. These TPD strategies have continuously enriched the toolbox for targeted protein degradation and expanded the scope of application, providing new ideas for biological research and drug discovery. This review attempts to introduce up-to-date research progress in the TPD strategies, focusing mainly on their design concepts, advantages, potential applications, and challenges, which may provide some inspiration for drug design, drug discovery, and clinical application for biologists and chemists.
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Affiliation(s)
- Zumei Wu
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yulong Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jinyun Dong
- Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China.
| | - Jiang-Jiang Qin
- Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China.
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Zhang J, Liu S, Li Y, Xu G, Deng H, King-Jones K, Li S. Nutrient status alters developmental fates via a switch in mitochondrial homeodynamics. Nat Commun 2025; 16:1258. [PMID: 39893174 PMCID: PMC11787341 DOI: 10.1038/s41467-025-56528-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 01/15/2025] [Indexed: 02/04/2025] Open
Abstract
Steroid hormones are powerful endocrine regulators, but little is known about how environmental conditions modulate steroidogenesis to reprogram developmental fates. Here, we use the Drosophila prothoracic gland (PG) to investigate how a nutrient restriction checkpoint (NRC) ensures or blocks developmental progression and sexual maturation via regulating steroidogenesis. Extensive transcriptome analysis of the PG reveals that pre-NRC starvation significantly downregulates mitochondria-associated genes. Pre-NRC starvation reduces prothoracicotropic neuropeptide hormone signaling, insulin signaling, and TORC1 activity in PG cells, which prevent mitochondrial fragmentation and import of Disembodied, a key steroidogenic enzyme. Ultimately, pre-NRC starvation causes severe mitophagy and proteasome dysfunction, blocking steroidogenesis and metamorphosis. By contrast, post-NRC starvation does not impair mitochondrial homeostasis in PG cells but reduces sit expression and induces moderate autophagy to promote steroidogenesis, leading to precocious metamorphosis. This study constitutes a paradigm for exploring how steroid hormone levels are controlled in response to environmental stress during developmental checkpoints.
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Affiliation(s)
- Jie Zhang
- Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Suning Liu
- Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China.
- Guangmeiyuan R&D Center, Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, South China Normal University, Meizhou, China.
| | - Yang Li
- Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Guanfeng Xu
- Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Huimin Deng
- Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China
| | - Kirst King-Jones
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.
| | - Sheng Li
- Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology & School of Life Sciences, South China Normal University, Guangzhou, China.
- Guangmeiyuan R&D Center, Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology, South China Normal University, Meizhou, China.
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Yang L, Xiao L, Gao W, Huang X, Wei F, Zhang Q, Xiao Y. Macrophages at Low-Inflammatory Status Improved Osteogenesis via Autophagy Regulation. Tissue Eng Part A 2024; 30:e766-e779. [PMID: 33678009 DOI: 10.1089/ten.tea.2021.0015] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Accumulating evidence indicates that the interaction between immune and skeletal systems is vital in bone homeostasis. However, the detailed mechanisms between macrophage polarization and osteogenic differentiation of mesenchymal stromal cells (bone marrow-derived stromal cells [BMSCs]) remain largely unknown. We observed enhanced macrophage infiltration along with bone formation in vivo, which showed a transition from early-stage M1 phenotype to later stage M2 phenotype, cells at the transitional stage expressed both M1 and M2 markers that actively participated in osteogenesis, which was mimicked by stimulating macrophages with lower inflammatory stimulus (compared with typical M1). Using conditioned medium (CM) from M0, typical M1, low-inflammatory M1 (M1semi), and M2 macrophages, it was found that BMSCs treated with M1semi CM showed significantly induced migration, osteogenic differentiation, and mineralization, compared with others. Along with the induced osteogenesis, the autophagy level was the highest in M1semi CM-treated BMSCs, which was responsible for BMSC migration and osteogenic differentiation, as autophagy interruption significantly abolished this effect. This study indicated that low-inflammatory macrophages could activate autophagy in BMSCs to improve osteogenesis.
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Affiliation(s)
- Lan Yang
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
| | - Lan Xiao
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Australia
| | - Wendong Gao
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
| | - Xin Huang
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
| | - Fei Wei
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
| | - Qing Zhang
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yin Xiao
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
- The Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM), Queensland University of Technology, Brisbane, Australia
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Wang X, Shuai W, Yang P, Liu Y, Zhang Y, Wang G. Targeted protein degradation: expanding the technology to facilitate the clearance of neurotoxic proteins in neurodegenerative diseases. Ageing Res Rev 2024; 102:102584. [PMID: 39551160 DOI: 10.1016/j.arr.2024.102584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 10/30/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
In neurodegenerative diseases (NDDs), disruptions in protein homeostasis hinder the clearance of misfolded proteins, causing the formation of misfolded protein oligomers and multimers. The accumulation of these abnormal proteins results in the onset and progression of NDDs. Removal of non-native protein is essential for cell to maintain proteostasis. In recent years, targeted protein degradation (TPD) technologies have become a novel means of treating NDDs by removing misfolded proteins through the intracellular protein quality control system. The TPD strategy includes the participation of two primary pathways, namely the ubiquitin-proteasome pathway (for instance, PROTAC, molecular glue and hydrophobic tag), and the autophagy-lysosome pathway (such as LYTAC, AUTAC and ATTEC). In this review, we systematically present the mechanisms of various TPD strategies employed for neurotoxic protein degradation in NDDs. The article provides an overview of the design, in vitro and in vivo anti-NDD activities and pharmacokinetic properties of these small-molecular degraders. Finally, the advantages, challenges and perspectives of these TPD technologies in NDDs therapy are discussed, providing ideas for further development of small molecule degraders in the realm of NDDs.
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Affiliation(s)
- Xin Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Wen Shuai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Panpan Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Yinyang Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China
| | - Yiwen Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China.
| | - Guan Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University /West China School of Nursing, Sichuan University, Chengdu 610041, China.
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5
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Tang ZQ, Tang YL, Qin K, Li Q, Chen G, Huang YB, Li JJ. Overexpression of proteasome 26S subunit non-ATPase 6 protein and its clinicopathological significance in intrahepatic cholangiocarcinoma. World J Hepatol 2024; 16:1282-1289. [PMID: 39606161 PMCID: PMC11586755 DOI: 10.4254/wjh.v16.i11.1282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/23/2024] [Accepted: 07/23/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Currently, intrahepatic cholangiocarcinoma (ICC) poses a continuing, significant health challenge, but the relationship has yet to be established between ICC and the proteasome 26S subunit non-ATPase 6 (PSMD6). AIM To investigate the protein expression and clinicopathological significance of PSMD6 in ICC. METHODS The potential impact of the PSMD6 gene on the growth of ICC cell lines was analyzed using clustered regularly interspaced short palindromic repeat knockout screening technology. Forty-two paired specimens of ICC and adjacent non-cancerous tissues were collected. PSMD6 protein expression was determined by immunohistochemistry. Receiver operating characteristic curve analysis was performed to validate PSMD6 expression level, and its association with ICC patients' various clinicopathological characteristics was investigated. RESULTS The PSMD6 gene was found to be essential for the growth of ICC cell lines. PSMD6 protein was significantly overexpressed in ICC tissues (P < 0.001), but showed no significant association with patient age, gender, pathological grade, or tumor-node-metastasis stage (P > 0.05). CONCLUSION PSMD6 can promote the growth of ICC cells, thus playing a pro-oncogenic role.
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Affiliation(s)
- Zhong-Qing Tang
- Department of Pathology, Wuzhou Gongren Hospital/The Seventh Affiliated Hospital of Guangxi Medical University, Wuzhou 543000, Guangxi Zhuang Autonomous Region, China
| | - Yu-Lu Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Kai Qin
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Qi Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Bin Huang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Jian-Jun Li
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China.
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6
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Seabrook LJ, Franco CN, Loy CA, Osman J, Fredlender C, Zimak J, Campos M, Nguyen ST, Watson RL, Levine SR, Khalil MF, Sumigray K, Trader DJ, Albrecht LV. Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins. Nat Chem Biol 2024:10.1038/s41589-024-01741-y. [PMID: 39414979 DOI: 10.1038/s41589-024-01741-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 09/05/2024] [Indexed: 10/18/2024]
Abstract
A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates-glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders.
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Affiliation(s)
- Laurence J Seabrook
- Department of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
| | - Carolina N Franco
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Cody A Loy
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Jaida Osman
- Department of Chemistry, School of Physical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Callie Fredlender
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Jan Zimak
- Center for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA
| | - Melissa Campos
- Department of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
| | - Steven T Nguyen
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Richard L Watson
- Department of Medicine, Division of Pulmonary & Critical Care, University of California, Los Angeles, Los Angeles, CA, USA
| | - Samantha R Levine
- Center for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA
| | - Marian F Khalil
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Kaelyn Sumigray
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Darci J Trader
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
- Department of Chemistry, School of Physical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Lauren V Albrecht
- Department of Developmental & Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA.
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
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7
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Bhattacharya A, Chatterji U. Exosomal misfolded proteins released by cancer stem cells: dual functions in balancing protein homeostasis and orchestrating tumor progression. Discov Oncol 2024; 15:392. [PMID: 39215782 PMCID: PMC11365921 DOI: 10.1007/s12672-024-01262-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
Cancer stem cells (CSCs), the master regulators of tumor heterogeneity and progression, exert profound influence on cancer metastasis, via various secretory vesicles. Emerging from CSCs, the exosomes serve as pivotal mediators of intercellular communication within the tumor microenvironment, modulating invasion, angiogenesis, and immune responses. Moreover, CSC-derived exosomes play a central role in sculpting a dynamic landscape, contributing to the malignant phenotype. Amidst several exosomal cargoes, misfolded proteins have recently gained attention for their dual functions in maintaining protein homeostasis and promoting tumor progression. Disrupting these communication pathways could potentially prevent the maintenance and expansion of CSCs, overcome treatment resistance, and inhibit the supportive environment created by the tumor microenvironment, thereby improving the effectiveness of cancer therapies and reducing the risk of tumor recurrence and metastasis. Additionally, exosomes have also shown potential therapeutic applications, such as in drug delivery or as biomarkers for cancer diagnosis and prognosis. Therefore, comprehending the biology of exosomes derived from CSCs is a multifaceted area of research with implications in both basic sciences and clinical applications. This review explores the intricate interplay between exosomal misfolded proteins released by CSCs, the potent contributor in tumor heterogeneity, and their impact on cellular processes, shedding light on their role in cancer progression.
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Affiliation(s)
- Anuran Bhattacharya
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal, 700019, India
| | - Urmi Chatterji
- Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, West Bengal, 700019, India.
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8
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Hou D, Yu D, Yang G, Hu Y, Li H. Research progress in deubiquitinase OTUD3. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:1341-1352. [PMID: 39788523 PMCID: PMC11628234 DOI: 10.11817/j.issn.1672-7347.2024.230581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
OTU domain-containing protein 3 (OTUD3) is a crucial deubiquitinase that exhibits significant expression differences across various disease models. OTUD3 plays a role in regulating biological functions such as apoptosis, inflammatory responses, cell cycle, proliferation, and invasion in different cell types. By deubiquitinating key substrate proteins, OTUD3 is involved in essential physiological and pathological processes, including innate antiviral immunity, neural development, neurodegenerative diseases, and cancer. OTUD3 exhibits tumor-suppressive effects in breast cancer, esophageal cancer, colon cancer, and papillary thyroid cancer, but acts as an oncogenic in liver and lung cancers. OTUD3 serves as a biomarker in predicting diagnosing, and assessing prognosis for certain malignancies. Despite its potential, the molecular mechanisms of OTUD3 in many diseases are still not well-understood, and exploring OTUD3's regulatory mechanisms is essential for comprehending its roles in immunity and disease. Future research will focus on developing OTUD3-targeted therapies.
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Affiliation(s)
- Dan Hou
- Department of Neurology, Haikou Affiliated Hospital of Xiangya School of Medicine, Central South University, Haikou 570208.
| | - Dan Yu
- Department of Neurology, Haikou Affiliated Hospital of Xiangya School of Medicine, Central South University, Haikou 570208.
| | - Guoshuai Yang
- Department of Neurology, Haikou Affiliated Hospital of Xiangya School of Medicine, Central South University, Haikou 570208
| | - Yujie Hu
- Department of Neurology, Haikou Affiliated Hospital of Xiangya School of Medicine, Central South University, Haikou 570208
| | - Hongxin Li
- School of Economics and Management, Beijing Forestry University, Beijing 100083, China
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Jagtap YA, Kumar P, Dubey AR, Kinger S, Choudhary A, Karmakar S, Lal G, Kumar A, Kumar A, Prasad A, Mishra A. Acetaminophen induces mitochondrial apoptosis through proteasome dysfunctions. Life Sci 2024; 349:122732. [PMID: 38768775 DOI: 10.1016/j.lfs.2024.122732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/12/2024] [Accepted: 05/15/2024] [Indexed: 05/22/2024]
Abstract
Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency.
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Affiliation(s)
- Yuvraj Anandrao Jagtap
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Prashant Kumar
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Ankur Rakesh Dubey
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Sumit Kinger
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Akash Choudhary
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India
| | - Surojit Karmakar
- National Centre for Cell Science (NCCS), Ganeshkhind, Pune, Maharashtra, 411007, India
| | - Girdhari Lal
- National Centre for Cell Science (NCCS), Ganeshkhind, Pune, Maharashtra, 411007, India
| | - Awanish Kumar
- Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh, 492010, India
| | - Amit Kumar
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, 453552, India
| | - Amit Prasad
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh, 175005, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342037, India.
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10
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Davoody S, Asgari Taei A, Khodabakhsh P, Dargahi L. mTOR signaling and Alzheimer's disease: What we know and where we are? CNS Neurosci Ther 2024; 30:e14463. [PMID: 37721413 PMCID: PMC11017461 DOI: 10.1111/cns.14463] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/19/2023] Open
Abstract
Despite the great body of research done on Alzheimer's disease, the underlying mechanisms have not been vividly investigated. To date, the accumulation of amyloid-beta plaques and tau tangles constitutes the hallmark of the disease; however, dysregulation of the mammalian target of rapamycin (mTOR) seems to be significantly involved in the pathogenesis of the disease as well. mTOR, as a serine-threonine protein kinase, was previously known for controlling many cellular functions such as cell size, autophagy, and metabolism. In this regard, mammalian target of rapamycin complex 1 (mTORC1) may leave anti-aging impacts by robustly inhibiting autophagy, a mechanism that inhibits the accumulation of damaged protein aggregate and dysfunctional organelles. Formation and aggregation of neurofibrillary tangles and amyloid-beta plaques seem to be significantly regulated by mTOR signaling. Understanding the underlying mechanisms and connection between mTOR signaling and AD may suggest conducting clinical trials assessing the efficacy of rapamycin, as an mTOR inhibitor drug, in managing AD or may help develop other medications. In this literature review, we aim to elaborate mTOR signaling network mainly in the brain, point to gaps of knowledge, and define how and in which ways mTOR signaling can be connected with AD pathogenesis and symptoms.
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Affiliation(s)
- Samin Davoody
- Student Research Committee, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Afsaneh Asgari Taei
- Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Pariya Khodabakhsh
- Department of NeurophysiologyInstitute of Physiology, Eberhard Karls University of TübingenTübingenGermany
| | - Leila Dargahi
- Neurobiology Research CenterShahid Beheshti University of Medical SciencesTehranIran
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11
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Korhonen E. Inflammasome activation in response to aberrations of cellular homeostasis in epithelial cells from human cornea and retina. Acta Ophthalmol 2024; 102 Suppl 281:3-68. [PMID: 38386419 DOI: 10.1111/aos.16646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 01/16/2024] [Indexed: 02/24/2024]
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12
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Gutierrez-Merino C. Brain Hydrophobic Peptides Antagonists of Neurotoxic Amyloid β Peptide Monomers/Oligomers-Protein Interactions. Int J Mol Sci 2023; 24:13846. [PMID: 37762148 PMCID: PMC10531495 DOI: 10.3390/ijms241813846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/02/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Amyloid β (Aβ) oligomers have been linked to Alzheimer's disease (AD) pathogenesis and are the main neurotoxic forms of Aβ. This review focuses on the following: (i) the Aβ(1-42):calmodulin interface as a model for the design of antagonist Aβ peptides and its limitations; (ii) proteolytic degradation as the major source of highly hydrophobic peptides in brain cells; and (iii) brain peptides that have been experimentally demonstrated to bind to Aβ monomers or oligomers, Aβ fibrils, or Aβ plaques. It is highlighted that the hydrophobic amino acid residues of the COOH-terminal segment of Aβ(1-42) play a key role in its interaction with intracellular protein partners linked to its neurotoxicity. The major source of highly hydrophobic endogenous peptides of 8-10 amino acids in neurons is the proteasome activity. Many canonical antigen peptides bound to the major histocompatibility complex class 1 are of this type. These highly hydrophobic peptides bind to Aβ and are likely to be efficient antagonists of the binding of Aβ monomers/oligomers concentrations in the nanomolar range with intracellular proteins. Also, their complexation with Aβ will protect them against endopeptidases, suggesting a putative chaperon-like physiological function for Aβ that has been overlooked until now. Remarkably, the hydrophobic amino acid residues of Aβ responsible for the binding of several neuropeptides partially overlap with those playing a key role in its interaction with intracellular protein partners that mediates its neurotoxicity. Therefore, these latter neuropeptides are also potential candidates to antagonize Aβ peptides binding to target proteins. In conclusion, the analysis performed in this review points out that hydrophobic endogenous brain neuropeptides could be valuable biomarkers to evaluate the risk of the onset of sporadic AD, as well as for the prognosis of AD.
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Affiliation(s)
- Carlos Gutierrez-Merino
- Instituto de Biomarcadores de Patologías Moleculares, Universidad de Extremadura, 06006 Badajoz, Spain
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13
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Suthar SK, Lee SY. Truncation or proteolysis of α-synuclein in Parkinsonism. Ageing Res Rev 2023; 90:101978. [PMID: 37286088 DOI: 10.1016/j.arr.2023.101978] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 05/28/2023] [Accepted: 06/03/2023] [Indexed: 06/09/2023]
Abstract
Posttranslational modifications of α-synuclein, such as truncation or abnormal proteolysis, are implicated in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). A key focus of this article includes the proteases responsible for inducing truncation, the specific sites susceptible to truncation, and the resultant influence of these truncated species on the seeding and aggregation of endogenous α-synuclein. We also shed light on the unique structural attributes of these truncated species, and how these modifications can lead to distinctive forms of synucleinopathies. In addition, we explore the comparative toxic potentials of various α-synuclein species. An extensive analysis of available evidence of truncated α-synuclein species in human-synucleinopathy brains is also provided. Lastly, we delve into the detrimental impact of truncated species on key cellular structures such as the mitochondria and endoplasmic reticulum. Our article discusses enzymes involved in α-synuclein truncation, including 20 S proteasome, cathepsins, asparagine endopeptidase, caspase-1, calpain-1, neurosin/kallikrein-6, matrix metalloproteinase-1/-3, and plasmin. Truncation patterns impact α-synuclein aggregation - C-terminal truncation accelerates aggregation with larger truncations correlated with shortened aggregation lag times. N-terminal truncation affects aggregation differently based on the truncation location. C-terminally truncated α-synuclein forms compact, shorter fibrils compared to the full-length (FL) protein. N-terminally truncated monomers form fibrils similar in length to FL α-synuclein. Truncated forms show distinct fibril morphologies, increased β-sheet structures, and greater protease resistance. Misfolded α-synuclein can adopt various conformations, leading to unique aggregates and distinct synucleinopathies. Fibrils, with prion-like transmission, are potentially more toxic than oligomers, though this is still debated. Different α-synuclein variants with N- and C-terminal truncations, namely 5-140, 39-140, 65-140, 66-140, 68-140, 71-140, 1-139, 1-135, 1-133, 1-122, 1-119, 1-115, 1-110, and 1-103 have been found in PD, DLB, and MSA patients' brains. In Parkinsonism, excess misfolded α-synuclein overwhelms the proteasome degradation system, resulting in truncated protein production and accumulation in the mitochondria and endoplasmic reticulum.
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Affiliation(s)
| | - Sang-Yoon Lee
- Neuroscience Research Institute, Gachon University, Incheon, South Korea; Department of Neuroscience, College of Medicine, Gachon University, Incheon, South Korea.
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14
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Ma C, Yu R, Li J, Chao J, Liu P. Targeting proteostasis network in osteoporosis: Pathological mechanisms and therapeutic implications. Ageing Res Rev 2023; 90:102024. [PMID: 37532006 DOI: 10.1016/j.arr.2023.102024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 07/11/2023] [Accepted: 07/28/2023] [Indexed: 08/04/2023]
Abstract
As the most common bone disease, osteoporosis (OP) increases bone fragility and makes patients more vulnerable to the threat of osteoporotic fractures. With the ageing population in today's society, OP has become a huge and growing public health problem. Unfortunately, the clear pathogenesis of OP is still under exploration, and effective interventions are still scarce. Therefore, exploring new targets for pharmacological interventions to develop promising therapeutic drugs for OP is of great clinical value. Previous studies have shown that normal bone remodeling depends on proteostasis, whereas loss of proteostasis during ageing leads to the dysfunctional proteostasis network (PN) that fails to maintain bone homeostasis. Nevertheless, only a few studies have revealed the pathophysiological relationship between bone metabolism and a single component of PN, yet the role of PN as a whole in the pathogenesis of OP is still under investigation. This review comprehensively summarized the role of PN in the pathogenesis of OP and further discussed the potential of PN as innovative drug targets for the therapy of OP.
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Affiliation(s)
- Cong Ma
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China; Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ronghui Yu
- Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Junhong Li
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiashuo Chao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Ping Liu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China.
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15
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Begum R, Thota S, Batra S. Interplay between proteasome function and inflammatory responses in e-cig vapor condensate-challenged lung epithelial cells. Arch Toxicol 2023; 97:2193-2208. [PMID: 37344694 DOI: 10.1007/s00204-023-03504-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 04/20/2023] [Indexed: 06/23/2023]
Abstract
Exposure to cigarettes and other nicotine-based products results in persistent inflammation in the lung. In recent years, electronic cigarettes (e-cigs) have become extremely popular among adults and youth alike. E-cigarette vapor-induced oxidative stress promotes protein breakdown, DNA damage and cell death, culminating in a variety of respiratory diseases. The proteasome, a multi-catalytic protease, superintends protein degradation within the cell. When cells are stimulated with inflammatory cytokines such as IFN-γ and TNF-α, the constitutive catalytic proteasome subunits are replaced by the inducible subunits-low-molecular mass polypeptide (LMP)2 (β1i), multi-catalytic endopeptidase complex-like (MECL)1 (β2i), and LMP7 (β5i), which are required for the production of certain MHC class I-restricted T-cell epitopes. In this study, we used human alveolar epithelial cells (A549) and exposed them to filtered air or (1%) tobacco-flavored (TF) electronic cigarette vapor condensate (ECVC) ± nicotine (6 mg/ml) (TF-ECVC ± N) for 24 h. We observed an increase in the levels of IFN-γ, TNF-α, and inducible proteasome subunits (LMP7/PSMB8, LMP2/PSMB9, MECL1/PSMB10), and a reduced expression of constitutive proteasome subunits (β1/PSMB6 and β2/PSMB7) in challenged A549 cells. Interestingly, knockdown of the inducible proteasome subunit LMP7 reversed ECVC-induced expression of NADPH oxidase and immunoproteasome subunits in A549 cells. In addition, pre-exposure to an LMP7 inhibitor (ONX-0914) abrogated the mRNA expression of several NOX subunits and rescued the excessive production/release of inflammatory cytokines/chemokines (IL-6, IL-8, CCL2, and CCL5) in ECVC-challenged cells. Our findings suggest an important role of LMP7 in regulating the expression of inflammatory mediators during ECVC exposure. Overall, our results provide evidence for proteasome-dependent ROS-mediated inflammation in ECVC-challenged cells.
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Affiliation(s)
- R Begum
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, 129 Health Research Center, Baton Rouge, Louisiana, 70813, USA
| | - S Thota
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, 129 Health Research Center, Baton Rouge, Louisiana, 70813, USA
| | - S Batra
- Laboratory of Pulmonary Immunotoxicology, Department of Environmental Toxicology, Southern University and A&M College, 129 Health Research Center, Baton Rouge, Louisiana, 70813, USA.
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16
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Ding L, Chu W, Xia Y, Shi M, Li T, Zhou FQ, Deng DYB. UCHL1 facilitates protein aggregates clearance to enhance neural stem cell activation in spinal cord injury. Cell Death Dis 2023; 14:479. [PMID: 37507386 PMCID: PMC10382505 DOI: 10.1038/s41419-023-06003-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 07/12/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023]
Abstract
Activation of endogenous neural stem cells (NSCs) is greatly significant for the adult neurogenesis; however, it is extremely limited in the spinal cord after injury. Recent evidence suggests that accumulation of protein aggregates impairs the ability of quiescent NSCs to activate. Ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, plays critical roles in protein aggregations clearance, but its effects on NSC activation remains unknown. Here, we show that UCHL1 promotes NSC activation by clearing protein aggregates through ubiquitin-proteasome approach. Upregulation of UCHL1 facilitated the proliferation of spinal cord NSCs after spinal cord injury (SCI). Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and proteasome activity via C3/C3aR signaling, led to increased abundances of protein aggregations and decreased NSC proliferation. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway enhanced NSC activation post-SCI by reserving UCHL1 and proteasome functions. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets and new insights for NSC fate regulation.
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Affiliation(s)
- Lu Ding
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Weiwei Chu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Yu Xia
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Ming Shi
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Tian Li
- Obstetrics and Gynecology Department, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Feng-Quan Zhou
- Department of Orthopaedic Surgery and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - David Y B Deng
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
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17
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RAB7A GTPase Is Involved in Mitophagosome Formation and Autophagosome-Lysosome Fusion in N2a Cells Treated with the Prion Protein Fragment 106-126. Mol Neurobiol 2023; 60:1391-1407. [PMID: 36449254 DOI: 10.1007/s12035-022-03118-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 11/03/2022] [Indexed: 12/02/2022]
Abstract
Failed communication between mitochondria and lysosomes causes dysfunctional mitochondria, which may induce mitochondria-related neurodegenerative diseases. Here, we show that RAB7A, a small GTPase of the Rab family, mediates the crosstalk between these two important organelles to maintain homeostasis in N2a cells treated with PrP106-126. Specifically, we demonstrate that mitophagy deficiency in N2a cells caused by PrP106-126 is associated with dysregulated RAB7A localization in mitochondria. Cells lacking RAB7A display decreased mitochondrial colocalization with lysosomes and significantly increased mitochondrial protein expression, resulting in inhibited mitophagy. In contrast, overexpression of GTP-bound RAB7A directly induces lysosome colocalization with mitochondria. Further study revealed that GTP-bound RAB7A protects mitochondrial homeostasis by supporting autophagosome biogenesis. Moreover, we suggest that depletion of RAB7A leads to gross morphological changes in lysosomes, which prevents autophagosome-lysosome fusion and interferes with the breakdown of autophagic cargo within lysosomes. Overexpression of GTP-bound RAB7A can also alleviate PrP106-126-induced morphological damage and dysfunction of mitochondria, reducing neuronal apoptosis. Collectively, our data demonstrate that RAB7A successfully drives mitochondria to the autophagosomal lumen for degradation, suggesting that the communication of proteotoxic stress from mitochondria to lysosomes requires RAB7A, as a signaling molecule, to establish a link between the disturbed mitochondrial network and its remodeling. These findings indicate that small molecules regulating mitophagy have the potential to modulate cellular homeostasis and the clinical course of neurodegenerative diseases. Proposed model of mitophagy regulated by RAB7A. (1) Accumulating PrP106-126 induced mitophagy. (2) RAB7A is recruited to mitochondria. (3) ATG5-12 and ATG9A (5) vesicles are recruited to the autophagosome formation sites in a RAB7A-dependent manner. The ATG5-12 complex recruits and anchors LC3-I to form active LC3-II (4), accelerating mitophagosomal formation. The ATG9A vesicles are thought to be a source of membranes for autophagosome assembly. The recruitment of proteins and lipids induces membrane expansion and subsequent closure to form the mitophagosome. (6) Maintenance of the normal low lysosomal PH depends on active (GTP-bound) RAB7A. (7) RAB7A recruits effector molecules responsible for tight membrane interactions, and directly or indirectly, the subsequent autophagosome merges with the lysosome, and the cargo is completely degraded.
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18
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Cassidy K, Zhao H. Redefining the Scope of Targeted Protein Degradation: Translational Opportunities in Hijacking the Autophagy-Lysosome Pathway. Biochemistry 2023; 62:580-587. [PMID: 34569233 DOI: 10.1021/acs.biochem.1c00330] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The advent of multi-specific targeted protein degradation (TPD) therapies has made it possible to drug targets that have long been considered to be inaccessible. For this reason, the foremost TPD modalities - molecular glues and proteolysis targeting chimeras (PROTACs) -have been widely adopted and developed in therapeutic programs across the pharmaceutical and biotechnology industries. While there are many clear advantages to these two approaches, there are also blind spots. Specifically, PROTACs and molecular glues are inherently mechanistically analogous in that targets of both are degraded via the 26s proteasome; however, not all disease-relevant targets are suitable for ubiquitin proteasome system (UPS)-mediated degradation. The alternative mammalian protein degradation pathway, the autophagy-lysosome system (or ALS), is capable of degrading targets that elude the UPS such as long-lived proteins, insoluble protein aggregates, and even abnormal organelles. Emerging TPD strategies- such as ATTEC, AUTAC, and LYTAC- take advantage of the substrate diversity of the ALS to greatly expand the clinical utility of TPD. In this Perspective, we will discuss the array of current TPD modalities, with a focus on critical evaluation of these novel ALS-mediated degradation techniques.
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Affiliation(s)
- Katelyn Cassidy
- Discovery Biology, BioPharmaceuticals R&D, AstraZeneca, Waltham, Massachusetts 02451, United States
| | - Heng Zhao
- Discovery Biology, BioPharmaceuticals R&D, AstraZeneca, Waltham, Massachusetts 02451, United States
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19
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Goh J, Wong E, Soh J, Maier AB, Kennedy BK. Targeting the molecular & cellular pillars of human aging with exercise. FEBS J 2023; 290:649-668. [PMID: 34968001 DOI: 10.1111/febs.16337] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 10/29/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023]
Abstract
Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified seven biological pillars of aging and a consensus review, "Geroscience: Linking Aging to Chronic Disease," was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus represent a useful framework with which to study human aging. In this present review, we revisit the seven pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.
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Affiliation(s)
- Jorming Goh
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore
| | - Esther Wong
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore
| | - Janjira Soh
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
| | - Andrea Britta Maier
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Department of Medicine, National University of Singapore, Singapore.,Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia.,Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands
| | - Brian Keith Kennedy
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
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20
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Jain M, Patil N, Abdi G, Abbasi Tarighat M, Mohammed A, Ahmad Mohd Zain MR, Goh KW. Mechanistic Insights and Potential Therapeutic Approaches in PolyQ Diseases via Autophagy. Biomedicines 2023; 11:biomedicines11010162. [PMID: 36672670 PMCID: PMC9856063 DOI: 10.3390/biomedicines11010162] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 01/11/2023] Open
Abstract
Polyglutamine diseases are a group of congenital neurodegenerative diseases categorized with genomic abnormalities in the expansion of CAG triplet repeats in coding regions of specific disease-related genes. Protein aggregates are the toxic hallmark for polyQ diseases and initiate neuronal death. Autophagy is a catabolic process that aids in the removal of damaged organelles or toxic protein aggregates, a process required to maintain cellular homeostasis that has the potential to fight against neurodegenerative diseases, but this pathway gets affected under diseased conditions, as there is a direct impact on autophagy-related gene expression. The increase in the accumulation of autophagy vesicles reported in neurodegenerative diseases was due to an increase in autophagy or may have been due to a decrease in autophagy flux. These reports suggested that there is a contribution of autophagy in the pathology of diseases and regulation in the process of autophagy. It was demonstrated in various disease models of polyQ diseases that autophagy upregulation by using modulators can enhance the dissolution of toxic aggregates and delay disease progression. In this review, interaction of the autophagy pathway with polyQ diseases was analyzed, and a therapeutic approach with autophagy inducing drugs was established for disease pathogenesis.
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Affiliation(s)
- Mukul Jain
- Department of Lifesciences, Parul Institute of Applied Sciences, Parul University, Vadodara 391760, India
- Lab 209 Cell and Developmental Biology Lab, Centre of Research for Development, Parul University, Vadodara 391760, India
| | - Nil Patil
- Department of Lifesciences, Parul Institute of Applied Sciences, Parul University, Vadodara 391760, India
- Lab 209 Cell and Developmental Biology Lab, Centre of Research for Development, Parul University, Vadodara 391760, India
| | - Gholamreza Abdi
- Department of Biotechnology, Persian Gulf Research Institute, Persian Gulf University, Bushehr, 75169, Iran
- Correspondence: (G.A.); (M.R.A.M.Z.); (K.W.G.)
| | - Maryam Abbasi Tarighat
- Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr 75169, Iran
| | - Arifullah Mohammed
- Department of Agriculture, Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Jeli 17600, Malaysia
| | - Muhammad Rajaei Ahmad Mohd Zain
- Department of Orthopaedics, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
- Correspondence: (G.A.); (M.R.A.M.Z.); (K.W.G.)
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Malaysia
- Correspondence: (G.A.); (M.R.A.M.Z.); (K.W.G.)
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21
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Ghosh S, Ramadas B, Manna D. Targeted protein degradation using the lysosomal pathway. RSC Med Chem 2022; 13:1476-1494. [PMID: 36561077 PMCID: PMC9749926 DOI: 10.1039/d2md00273f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Degradation strategies have shown enormous promise after the inception of molecules like PROTACs (PRoteolysis TArgeting Chimeras) that induce the degradation of the substrate of choice rather than depending on blocking their catalytic activity like conventional inhibitory drugs. Over the past two decades, the application of PROTACs has made quite an impact, even reaching clinical translations. However, a major class of macromolecular targets, be that large proteins, aggregates, organelles or non-protein substrates, remain untouched when utilizing the ubiquitin-proteasomal pathway of degradation. In this review, we have attempted to cover modalities of targeted degradation that instead focus on recruiting the lysosomal pathway of degradation, which is gaining importance and being explored extensively as alternate and efficient approaches for treating disease-related milieus.
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Affiliation(s)
- Samrajni Ghosh
- Department of Chemistry, Indian Institute of Science Education and Research Bhopal Bhopal Bypass Road, Bhauri Bhopal-462066 MP India
| | - Bhavana Ramadas
- Department of Chemistry, Indian Institute of Science Education and Research Bhopal Bhopal Bypass Road, Bhauri Bhopal-462066 MP India
| | - Debasish Manna
- Department of Chemistry, Indian Institute of Science Education and Research Bhopal Bhopal Bypass Road, Bhauri Bhopal-462066 MP India
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22
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Yang J, Tong T, Zhu C, Zhou M, Jiang Y, Chen H, Que L, Liu L, Zhu G, Ha T, Chen Q, Li C, Xu Y, Li J, Li Y. Peli1 contributes to myocardial ischemia/reperfusion injury by impairing autophagy flux via its E3 ligase mediated ubiquitination of P62. J Mol Cell Cardiol 2022; 173:30-46. [PMID: 36179399 DOI: 10.1016/j.yjmcc.2022.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 09/08/2022] [Accepted: 09/19/2022] [Indexed: 01/18/2023]
Abstract
Autophagy flux is impaired during myocardial ischemia/reperfusion (M-I/R) via the accumulation of autophagosome and insufficient clearance, which exacerbates cardiomyocyte death. Peli1 (Pellion1) is a RING finger domain-containing ubiquitin E3 ligase that could catalyze the polyubiquitination of substrate proteins. Peli1 has been demonstrated to play an important role in ischemic cardiac diseases. However, little is known about whether Peli1 is involved in the regulation of autophagy flux during M-I/R. The present study investigated whether M-I/R induced impaired autophagy flux could be mediated through Peli1 dependent mechanisms. We induced M-I/R injury in wild type (WT) and Peli1 knockout mice and observed that M-I/R significantly decreased cardiac function that was associated with increased cardiac Peli1 expression and upregulated autophagy-associated protein LC3II and P62. In contrast, Peli1 knockout mice exhibited significant improvement of M-I/R induced cardiac dysfunction and decreased LC3II and P62 expression. Besides, inhibitors of autophagy also increased the infarct size in Peli1 knockout mice after 24 h of reperfusion. Mechanistic studies demonstrated that in vivo I/R or in vitro hypoxia/reoxygenation (H/R) markedly increased the Peli1 E3 ligase activity which directly promoted the ubiquitination of P62 at lysine(K)7 via K63-linkage to inhibit its dimerization and autophagic degradation. Co-immunoprecipitation and GST-pull down assay indicated that Peli1 interacted with P62 via the Ring domain. In addition, Peli1 deficiency also decreased cardiomyocyte apoptosis. Together, our work demonstrated a critical link between increased expression and activity of Peli1 and autophagy flux blockage in M-I/R injury, providing insight into a promising strategy for treating myocardium M-I/R injury.
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Affiliation(s)
- Jie Yang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Tingting Tong
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Chenghao Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Miao Zhou
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Yuqing Jiang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Hao Chen
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Pathology, Wannan Medical College, Wuhu 241002, Anhui, China
| | - Linli Que
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Li Liu
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Guoqing Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Tuanzhu Ha
- Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA
| | - Qi Chen
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Chuanfu Li
- Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575, USA
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Institute of Biomedical Research, Liaocheng University, Liaocheng 252000, Shandong, China
| | - Jiantao Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
| | - Yuehua Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
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Intartaglia D, Giamundo G, Conte I. Autophagy in the retinal pigment epithelium: a new vision and future challenges. FEBS J 2022; 289:7199-7212. [PMID: 33993621 PMCID: PMC9786786 DOI: 10.1111/febs.16018] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/07/2021] [Accepted: 05/12/2021] [Indexed: 01/13/2023]
Abstract
The retinal pigment epithelium (RPE) is a highly specialized monolayer of polarized, pigmented epithelial cells that resides between the vessels of the choriocapillaris and the neural retina. The RPE is essential for the maintenance and survival of overlying light-sensitive photoreceptors, as it participates in the formation of the outer blood-retinal barrier, phagocytosis, degradation of photoreceptor outer segment (POS) tips, maintenance of the retinoid cycle, and protection against light and oxidative stress. Autophagy is an evolutionarily conserved 'self-eating' process, designed to maintain cellular homeostasis. The daily autophagy demands in the RPE require precise gene regulation for the digestion and recycling of intracellular and POS components in lysosomes in response to light and stress conditions. In this review, we discuss selective autophagy and focus on the recent advances in our understanding of the mechanism of cell clearance in the RPE for visual function. Understanding how this catabolic process is regulated by both transcriptional and post-transcriptional mechanisms in the RPE will promote the recognition of pathological pathways in genetic disease and shed light on potential therapeutic strategies to treat visual impairments in patients with retinal disorders associated with lysosomal dysfunction.
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Affiliation(s)
| | | | - Ivan Conte
- Telethon Institute of Genetics and MedicinePozzuoli (Naples)Italy,Department of BiologyUniversity of Naples Federico IINaplesItaly
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Profumo E, Maggi E, Arese M, Di Cristofano C, Salvati B, Saso L, Businaro R, Buttari B. Neuropeptide Y Promotes Human M2 Macrophage Polarization and Enhances p62/SQSTM1-Dependent Autophagy and NRF2 Activation. Int J Mol Sci 2022; 23:13009. [PMID: 36361795 PMCID: PMC9653849 DOI: 10.3390/ijms232113009] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 08/15/2023] Open
Abstract
Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals. Macrophage number and phenotype influence plaque fate. Here, we investigated the effect of NPY on the changes in phenotype and functions of human macrophages, from the pro-inflammatory phenotype M1 to the reparative M2, indicative of atherosclerosis regression or stabilization. Human monocytes were differentiated in vitro into macrophages with M-CSF (M0) and polarized towards an M1 phenotype with IFN-γ plus LPS M(IFN-γ/LPS) or M2 with IL-10 (M IL-10) and further challenged with NPY (10-7-10-9 M) for 8-36 h. Cell phenotype and functions were analyzed by immunofluorescence and immunochemical analyses. NPY affected macrophage surface markers and secretome profile expression, thus shifting macrophages toward an M2-like phenotype. NPY also prevented the impairment of endocytosis triggered by the oxysterol 7-keto-cholesterol (7KC) and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M0 macrophages. NPY-treated M0 macrophages enhanced the autophagosome formation by upregulating the cell content of the autophagy markers LC3-II and p62-SQSTM1, increased activation of the anti-oxidative transcription factor NRF2 (NF-E2-related factor 2), and subsequently induced its target gene HMOX1 that encodes heme oxygenase-1. Our findings indicate that NPY has a cytoprotective effect with respect to the progression of the inflammatory pathway, both enhancing p62/SQSTM1-dependent autophagy and the NRF2-antioxidant signaling pathway in macrophages. NPY signaling may have a crucial role in tissue homeostasis in host inflammatory responses through the regulation of macrophage balance and functions within atherosclerosis.
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Affiliation(s)
- Elisabetta Profumo
- Department of Cardiovascular and Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy
| | - Elisa Maggi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Marzia Arese
- Department of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, 00185 Rome, Italy
| | - Claudio Di Cristofano
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Bruno Salvati
- Department of Surgical Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Luciano Saso
- Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, 00185 Rome, Italy
| | - Rita Businaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy
| | - Brigitta Buttari
- Department of Cardiovascular and Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy
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25
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Zhu Y, Afolabi LO, Wan X, Shim JS, Chen L. TRIM family proteins: roles in proteostasis and neurodegenerative diseases. Open Biol 2022; 12:220098. [PMID: 35946309 PMCID: PMC9364147 DOI: 10.1098/rsob.220098] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 07/07/2022] [Indexed: 11/17/2022] Open
Abstract
Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.
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Affiliation(s)
- Yan Zhu
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing 100864, People's Republic of China
| | - Lukman O. Afolabi
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing 100864, People's Republic of China
| | - Xiaochun Wan
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing 100864, People's Republic of China
| | - Joong Sup Shim
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, People's Republic of China
| | - Liang Chen
- Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, People's Republic of China
- University of Chinese Academy of Sciences, Beijing 100864, People's Republic of China
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26
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Ruiz-Aparicio PF, Vernot JP. Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities. J Pers Med 2022; 12:jpm12050716. [PMID: 35629139 PMCID: PMC9147878 DOI: 10.3390/jpm12050716] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/27/2022] [Indexed: 12/17/2022] Open
Abstract
Bone marrow aging is associated with multiple cellular dysfunctions, including perturbed haematopoiesis, the propensity to haematological transformation, and the maintenance of leukaemia. It has been shown that instructive signals from different leukemic cells are delivered to stromal cells to remodel the bone marrow into a supportive leukemic niche. In particular, cellular senescence, a physiological program with both beneficial and deleterious effects on the health of the organisms, may be responsible for the increased incidence of haematological malignancies in the elderly and for the survival of diverse leukemic cells. Here, we will review the connection between BM aging and cellular senescence and the role that these processes play in leukaemia progression. Specifically, we discuss the role of mesenchymal stem cells as a central component of the supportive niche. Due to the specificity of the genetic defects present in leukaemia, one would think that bone marrow alterations would also have particular changes, making it difficult to envisage a shared therapeutic use. We have tried to summarize the coincident features present in BM stromal cells during aging and senescence and in two different leukaemias, acute myeloid leukaemia, with high frequency in the elderly, and B-acute lymphoblastic leukaemia, mainly a childhood disease. We propose that mesenchymal stem cells are similarly affected in these different leukaemias, and that the changes that we observed in terms of cellular function, redox balance, genetics and epigenetics, soluble factor repertoire and stemness are equivalent to those occurring during BM aging and cellular senescence. These coincident features may be used to explore strategies useful to treat various haematological malignancies.
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Affiliation(s)
- Paola Fernanda Ruiz-Aparicio
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
| | - Jean-Paul Vernot
- Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia;
- Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, Colombia
- Correspondence:
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27
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Montano M, Oursler KK, Xu K, Sun YV, Marconi VC. Biological ageing with HIV infection: evaluating the geroscience hypothesis. THE LANCET. HEALTHY LONGEVITY 2022; 3:e194-e205. [PMID: 36092375 PMCID: PMC9454292 DOI: 10.1016/s2666-7568(21)00278-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Although people with HIV are living longer, as they age they remain disproportionately burdened with multimorbidity that is exacerbated in resource-poor settings. The geroscience hypothesis postulates that a discrete set of between five and ten hallmarks of biological ageing drive multimorbidity, but these processes have not been systematically examined in the context of people with HIV. We examine four major hallmarks of ageing (macromolecular damage, senescence, inflammation, and stem-cell dysfunction) as gerodrivers in the context of people with HIV. As a counterbalance, we introduce healthy ageing, physiological reserve, intrinsic capacity, and resilience as promoters of geroprotection that counteract gerodrivers. We discuss emerging geroscience-based diagnostic biomarkers and therapeutic strategies, and provide examples based on recent advances in cellular senescence, and other, non-pharmacological approaches. Finally, we present a conceptual model of biological ageing in the general population and in people with HIV that integrates gerodrivers and geroprotectors as modulators of homoeostatic reserves and organ function over the lifecourse.
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28
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Sriwastva MK, Deng Z, Wang B, Teng Y, Kumar A, Sundaram K, Mu J, Lei C, Dryden GW, Xu F, Zhang L, Yan J, Zhang X, Park JW, Merchant ML, Egilmez NK, Zhang H. Exosome-like nanoparticles from Mulberry bark prevent DSS-induced colitis via the AhR/COPS8 pathway. EMBO Rep 2022; 23:e53365. [PMID: 34994476 PMCID: PMC8892346 DOI: 10.15252/embr.202153365] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 12/02/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Bark protects the tree against environmental insults. Here, we analyzed whether this defensive strategy could be utilized to broadly enhance protection against colitis. As a proof of concept, we show that exosome-like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)-mediated activation of the AhR signaling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium-specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti-microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter-kingdom communication in the mammalian intestine through an AhR-COPS8-mediated anti-inflammatory pathway. These data suggest that inflammatory pathways in a microbiota-enriched intestinal environment are regulated by COPS8 and that edible plant-derived ELNs may hold the potential as new agents for the prevention and treatment of gut-related inflammatory disease.
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Affiliation(s)
- Mukesh K Sriwastva
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Zhong‐Bin Deng
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Bomei Wang
- Department of Translational OncologyGenentechSan FranciscoCaliforniaUSA
| | - Yun Teng
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Anil Kumar
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Kumaran Sundaram
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Jingyao Mu
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Chao Lei
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Gerald W Dryden
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
- Robley Rex Veterans Affairs Medical CenterLouisvilleKYUSA
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKYUSA
| | - Fangyi Xu
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Lifeng Zhang
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Jun Yan
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Xiang Zhang
- KBRIN Bioinformatics CoreUniversity of LouisvilleLouisvilleKYUSA
| | - Juw Won Park
- KBRIN Bioinformatics CoreUniversity of LouisvilleLouisvilleKYUSA
- Department of Computer Engineering and Computer ScienceUniversity of LouisvilleLouisvilleKYUSA
| | - Michael L Merchant
- Kidney Disease Program and Clinical Proteomics CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Nejat K Egilmez
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
| | - Huang‐Ge Zhang
- Department of Microbiology & ImmunologyBrown Cancer CenterUniversity of LouisvilleLouisvilleKYUSA
- Robley Rex Veterans Affairs Medical CenterLouisvilleKYUSA
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29
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Petese A, Cesaroni V, Cerri S, Blandini F. Are Lysosomes Potential Therapeutic Targets for Parkinson's Disease? CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2022; 21:642-655. [PMID: 34370650 DOI: 10.2174/1871527320666210809123630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/16/2021] [Accepted: 06/10/2021] [Indexed: 06/13/2023]
Abstract
Parkinson´s Disease (PD) is the second most common neurodegenerative disorder, affecting ~2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy Bodies (LBs). Recently, Genome-Wide Association Studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.
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Affiliation(s)
- Alessandro Petese
- Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Valentina Cesaroni
- Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Silvia Cerri
- Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, Pavia, Italy
| | - Fabio Blandini
- Cellular and Molecular Neurobiology Unit, IRCCS Mondino Foundation, Pavia, Italy
- Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
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30
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S. Bell H, Tower J. In vivo assay and modelling of protein and mitochondrial turnover during aging. Fly (Austin) 2021; 15:60-72. [PMID: 34002678 PMCID: PMC8143256 DOI: 10.1080/19336934.2021.1911286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/29/2022] Open
Abstract
To maintain homoeostasis, cells must degrade damaged or misfolded proteins and synthesize functional replacements. Maintaining a balance between these processes, known as protein turnover, is necessary for stress response and cellular adaptation to a changing environment. Damaged mitochondria must also be removed and replaced. Changes in protein and mitochondrial turnover are associated with aging and neurodegenerative disease, making it important to understand how these processes occur and are regulated in cells. To achieve this, reliable assays of turnover must be developed. Several methods exist, including pulse-labelling with radioactive or stable isotopes and strategies making use of fluorescent proteins, each with their own advantages and limitations. Both cell culture and live animals have been used for these studies, in systems ranging from yeast to mammals. In vivo assays are especially useful for connecting turnover to aging and disease. With its short life cycle, suitability for fluorescent imaging, and availability of genetic tools, Drosophila melanogaster is particularly well suited for this kind of analysis.
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Affiliation(s)
- Hans S. Bell
- Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - John Tower
- Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
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31
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Upadhyay A. Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases. Acta Pharm Sin B 2021; 11:2995-3014. [PMID: 34729300 PMCID: PMC8546668 DOI: 10.1016/j.apsb.2021.01.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/12/2020] [Accepted: 11/03/2020] [Indexed: 01/13/2023] Open
Abstract
Cells have different sets of molecules for performing an array of physiological functions. Nucleic acids have stored and carried the information throughout evolution, whereas proteins have been attributed to performing most of the cellular functions. To perform these functions, proteins need to have a unique conformation and a definite lifespan. These attributes are achieved by a highly coordinated protein quality control (PQC) system comprising chaperones to fold the proteins in a proper three-dimensional structure, ubiquitin-proteasome system for selective degradation of proteins, and autophagy for bulk clearance of cell debris. Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery, leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions. However, modulating the expression and functional efficiency of molecular chaperones, E3 ubiquitin ligases, and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects. Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions. The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.
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Key Words
- 17-AAG, 17-allylamino-geldanamycin
- APC, anaphase-promoting complex
- Ageing
- Autophagy
- BAG, BCL2-associated athanogene
- CAP, chaperone-assisted proteasomal degradation
- CASA, chaperone-assisted selective autophagy
- CHIP, carboxy-terminus of HSC70 interacting protein
- CMA, chaperone-mediated autophagy
- Cancer
- Chaperones
- DUBs, deubiquitinases
- Drug discovery
- EGCG, epigallocatechin-3-gallate
- ESCRT, endosomal sorting complexes required for transport
- HECT, homologous to the E6-AP carboxyl terminus
- HSC70, heat shock cognate 70
- HSF1, heat shock factor 1
- HSP, heat shock protein
- KFERQ, lysine-phenylalanine-glutamate-arginine-glutamine
- LAMP2a, lysosome-associated membrane protein 2a
- LC3, light chain 3
- NBR1, next to BRCA1 gene 1
- Natural molecules
- Neurodegeneration
- PQC, protein quality control
- Proteinopathies
- Proteostasis
- RING, really interesting new gene
- UPS, ubiquitin–proteasome system
- Ub, ubiquitin
- Ubiquitin proteasome system
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Affiliation(s)
- Arun Upadhyay
- Department of Biochemistry, Central University of Rajasthan, Bandar Sindari, Kishangarh, Ajmer, Rajasthan 305817, India
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Li H, Dong J, Cai M, Xu Z, Cheng XD, Qin JJ. Protein degradation technology: a strategic paradigm shift in drug discovery. J Hematol Oncol 2021; 14:138. [PMID: 34488823 PMCID: PMC8419833 DOI: 10.1186/s13045-021-01146-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/24/2021] [Indexed: 01/10/2023] Open
Abstract
Targeting pathogenic proteins with small-molecule inhibitors (SMIs) has become a widely used strategy for treating malignant tumors. However, most intracellular proteins have been proven to be undruggable due to a lack of active sites, leading to a significant challenge in the design and development of SMIs. In recent years, the proteolysis-targeting chimeric technology and related emerging degradation technologies have provided additional approaches for targeting these undruggable proteins. These degradation technologies show a tendency of superiority over SMIs, including the rapid and continuous target consumption as well as the stronger pharmacological effects, being a hot topic in current research. This review mainly focuses on summarizing the development of protein degradation technologies in recent years. Their advantages, potential applications, and limitations are also discussed. We hope this review would shed light on the design, discovery, and clinical application of drugs associated with these degradation technologies.
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Affiliation(s)
- Haobin Li
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022 Zhejiang China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018 Zhejiang China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053 China
| | - Jinyun Dong
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022 Zhejiang China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018 Zhejiang China
| | - Maohua Cai
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022 Zhejiang China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018 Zhejiang China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053 China
| | - Zhiyuan Xu
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022 Zhejiang China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018 Zhejiang China
| | - Xiang-Dong Cheng
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022 Zhejiang China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018 Zhejiang China
| | - Jiang-Jiang Qin
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022 Zhejiang China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018 Zhejiang China
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053 China
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Corbet GA, Wheeler JR, Parker R, Weskamp K. TDP43 ribonucleoprotein granules: physiologic function to pathologic aggregates. RNA Biol 2021; 18:128-138. [PMID: 34412568 DOI: 10.1080/15476286.2021.1963099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Ribonucleoprotein (RNP) assemblies are ubiquitous in eukaryotic cells and have functions throughout RNA transcription, splicing, and stability. Of the RNA-binding proteins that form RNPs, TAR DNA-binding protein of 43 kD (TDP43) is of particular interest due to its essential nature and its association with disease. TDP43 plays critical roles in RNA metabolism, many of which require its recruitment to RNP granules such as stress granules, myo-granules, and neuronal transport granules. Moreover, the presence of cytoplasmic TDP43-positive inclusions is a pathological hallmark of several neurodegenerative diseases. Despite the pervasiveness of TDP43 aggregates, TDP43 mutations are exceedingly rare, suggesting that aggregation may be linked to dysregulation of TDP43 function. Oligomerization is a part of normal TDP43 function; thus, it is of interest to understand what triggers the irreversible aggregation that is seen in disease. Herein, we examine TDP43 functions, particularly in RNP granules, and the mechanisms which may explain pathological TDP43 aggregation.
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Affiliation(s)
- Giulia Ada Corbet
- Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA
| | | | - Roy Parker
- Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA.,Department of Chemistry, Howard Hughes Medical Institute, Chevy Chase, MD, USA
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Llamas E, Torres‐Montilla S, Lee HJ, Barja MV, Schlimgen E, Dunken N, Wagle P, Werr W, Zuccaro A, Rodríguez‐Concepción M, Vilchez D. The intrinsic chaperone network of Arabidopsis stem cells confers protection against proteotoxic stress. Aging Cell 2021; 20:e13446. [PMID: 34327811 PMCID: PMC8373342 DOI: 10.1111/acel.13446] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/25/2021] [Accepted: 07/08/2021] [Indexed: 01/21/2023] Open
Abstract
The biological purpose of plant stem cells is to maintain themselves while providing new pools of differentiated cells that form organs and rejuvenate or replace damaged tissues. Protein homeostasis or proteostasis is required for cell function and viability. However, the link between proteostasis and plant stem cell identity remains unknown. In contrast to their differentiated counterparts, we find that root stem cells can prevent the accumulation of aggregated proteins even under proteotoxic stress conditions such as heat stress or proteasome inhibition. Notably, root stem cells exhibit enhanced expression of distinct chaperones that maintain proteome integrity. Particularly, intrinsic high levels of the T-complex protein-1 ring complex/chaperonin containing TCP1 (TRiC/CCT) complex determine stem cell maintenance and their remarkable ability to suppress protein aggregation. Overexpression of CCT8, a key activator of TRiC/CCT assembly, is sufficient to ameliorate protein aggregation in differentiated cells and confer resistance to proteotoxic stress in plants. Taken together, our results indicate that enhanced proteostasis mechanisms in stem cells could be an important requirement for plants to persist under extreme environmental conditions and reach extreme long ages. Thus, proteostasis of stem cells can provide insights to design and breed plants tolerant to environmental challenges caused by the climate change.
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Affiliation(s)
- Ernesto Llamas
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - Salvador Torres‐Montilla
- Centre for Research in Agricultural Genomics (CRAG) CSIC‐IRTA‐UAB‐UBCampus UAB Bellaterra Barcelona Spain
| | - Hyun Ju Lee
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - María Victoria Barja
- Centre for Research in Agricultural Genomics (CRAG) CSIC‐IRTA‐UAB‐UBCampus UAB Bellaterra Barcelona Spain
| | - Elena Schlimgen
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - Nick Dunken
- Cluster of Excellence on Plant Sciences (CEPLAS) Institute for Plant Sciences University of Cologne Cologne Germany
| | - Prerana Wagle
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
| | - Wolfgang Werr
- Developmental Biology Biocenter University of Cologne Cologne Germany
| | - Alga Zuccaro
- Cluster of Excellence on Plant Sciences (CEPLAS) Institute for Plant Sciences University of Cologne Cologne Germany
| | - Manuel Rodríguez‐Concepción
- Centre for Research in Agricultural Genomics (CRAG) CSIC‐IRTA‐UAB‐UBCampus UAB Bellaterra Barcelona Spain
- Institute for Plant Molecular and Cell Biology (IBMCP) CSIC‐UPV Valencia Spain
| | - David Vilchez
- Cologne Excellence Cluster for Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Germany
- Center for Molecular Medicine Cologne (CMMC) University of Cologne Cologne Germany
- Faculty of Medicine University Hospital Cologne Cologne Germany
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Monroy Kuhn JM, Meusemann K, Korb J. Disentangling the aging gene expression network of termite queens. BMC Genomics 2021; 22:339. [PMID: 33975542 PMCID: PMC8114706 DOI: 10.1186/s12864-021-07649-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 04/22/2021] [Indexed: 02/07/2023] Open
Abstract
Background Most insects are relatively short-lived, with a maximum lifespan of a few weeks, like the aging model organism, the fruit-fly Drosophila melanogaster. By contrast, the queens of many social insects (termites, ants and some bees) can live from a few years to decades. This makes social insects promising models in aging research providing insights into how a long reproductive life can be achieved. Yet, aging studies on social insect reproductives are hampered by a lack of quantitative data on age-dependent survival and time series analyses that cover the whole lifespan of such long-lived individuals. We studied aging in queens of the drywood termite Cryptotermes secundus by determining survival probabilities over a period of 15 years and performed transcriptome analyses for queens of known age that covered their whole lifespan. Results The maximum lifespan of C. secundus queens was 13 years, with a median maximum longevity of 11.0 years. Time course and co-expression network analyses of gene expression patterns over time indicated a non-gradual aging pattern. It was characterized by networks of genes that became differentially expressed only late in life, namely after ten years, which associates well with the median maximum lifespan for queens. These old-age gene networks reflect processes of physiological upheaval. We detected strong signs of stress, decline, defense and repair at the transcriptional level of epigenetic control as well as at the post-transcriptional level with changes in transposable element activity and the proteostasis network. The latter depicts an upregulation of protein degradation, together with protein synthesis and protein folding, processes which are often down-regulated in old animals. The simultaneous upregulation of protein synthesis and autophagy is indicative of a stress-response mediated by the transcription factor cnc, a homolog of human nrf genes. Conclusions Our results show non-linear senescence with a rather sudden physiological upheaval at old-age. Most importantly, they point to a re-wiring in the proteostasis network and stress as part of the aging process of social insect queens, shortly before queens die. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07649-4.
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Affiliation(s)
- José Manuel Monroy Kuhn
- Department of Evolutionary Biology & Ecology, Institute of Biology I, Albert Ludwig University of Freiburg, Hauptstr. 1, D-79104, Freiburg (i. Brsg.), Germany. .,Computational Discovery Research, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, D-85764, Neuherberg, Germany.
| | - Karen Meusemann
- Department of Evolutionary Biology & Ecology, Institute of Biology I, Albert Ludwig University of Freiburg, Hauptstr. 1, D-79104, Freiburg (i. Brsg.), Germany.,Australian National Insect Collection, CSIRO National Research Collections Australia, Clunies Ross Street, Acton, ACT 2601, Canberra, Australia
| | - Judith Korb
- Department of Evolutionary Biology & Ecology, Institute of Biology I, Albert Ludwig University of Freiburg, Hauptstr. 1, D-79104, Freiburg (i. Brsg.), Germany.
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The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration. Cell Mol Life Sci 2021; 78:7257-7273. [PMID: 34677645 PMCID: PMC8629791 DOI: 10.1007/s00018-021-03962-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/24/2021] [Accepted: 09/24/2021] [Indexed: 01/17/2023]
Abstract
The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.
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Dash R, Ali MC, Jahan I, Munni YA, Mitra S, Hannan MA, Timalsina B, Oktaviani DF, Choi HJ, Moon IS. Emerging potential of cannabidiol in reversing proteinopathies. Ageing Res Rev 2021; 65:101209. [PMID: 33181336 DOI: 10.1016/j.arr.2020.101209] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 10/22/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022]
Abstract
The aberrant accumulation of disease-specific protein aggregates accompanying cognitive decline is a pathological hallmark of age-associated neurological disorders, also termed as proteinopathies, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. Along with oxidative stress and neuroinflammation, disruption in protein homeostasis (proteostasis), a network that constitutes protein surveillance system, plays a pivotal role in the pathobiology of these dementia disorders. Cannabidiol (CBD), a non-psychotropic phytocannabinoid of Cannabis sativa, is known for its pleiotropic neuropharmacological effects on the central nervous system, including the ability to abate oxidative stress, neuroinflammation, and protein misfolding. Over the past years, compelling evidence has documented disease-modifying role of CBD in various preclinical and clinical models of neurological disorders, suggesting the potential therapeutic implications of CBD in these disorders. Because of its putative role in the proteostasis network in particular, CBD could be a potent modulator for reversing not only age-associated neurodegeneration but also other protein misfolding disorders. However, the current understanding is insufficient to underpin this proposition. In this review, we discuss the potentiality of CBD as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing roles in the neurodegenerative disorders. We anticipate that the current effort will advance our knowledge on the implication of CBD in proteostasis network, opening up a new therapeutic window for aging proteinopathies.
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Lin TK, Lin KJ, Lin KL, Liou CW, Chen SD, Chuang YC, Wang PW, Chuang JH, Wang TJ. When Friendship Turns Sour: Effective Communication Between Mitochondria and Intracellular Organelles in Parkinson's Disease. Front Cell Dev Biol 2020; 8:607392. [PMID: 33330511 PMCID: PMC7733999 DOI: 10.3389/fcell.2020.607392] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 10/30/2020] [Indexed: 12/17/2022] Open
Abstract
Parkinson's disease (PD) is a complex neurodegenerative disease with pathological hallmarks including progressive neuronal loss from the substantia nigra pars compacta and α-synuclein intraneuronal inclusions, known as Lewy bodies. Although the etiology of PD remains elusive, mitochondrial damage has been established to take center stage in the pathogenesis of PD. Mitochondria are critical to cellular energy production, metabolism, homeostasis, and stress responses; the association with PD emphasizes the importance of maintenance of mitochondrial network integrity. To accomplish the pleiotropic functions, mitochondria are dynamic not only within their own network but also in orchestrated coordination with other organelles in the cellular community. Through physical contact sites, signal transduction, and vesicle transport, mitochondria and intracellular organelles achieve the goals of calcium homeostasis, redox homeostasis, protein homeostasis, autophagy, and apoptosis. Herein, we review the finely tuned interactions between mitochondria and surrounding intracellular organelles, with focus on the nucleus, endoplasmic reticulum, Golgi apparatus, peroxisomes, and lysosomes. Participants that may contribute to the pathogenic mechanisms of PD will be highlighted in this review.
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Affiliation(s)
- Tsu-Kung Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kai-Jung Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kai-Lieh Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chia-Wei Liou
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shang-Der Chen
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yao-Chung Chuang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Wen Wang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Metabolism, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jiin-Haur Chuang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tzu-Jou Wang
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Pediatric, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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39
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Bhattacharya K, Weidenauer L, Luengo TM, Pieters EC, Echeverría PC, Bernasconi L, Wider D, Sadian Y, Koopman MB, Villemin M, Bauer C, Rüdiger SGD, Quadroni M, Picard D. The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation. Nat Commun 2020; 11:5975. [PMID: 33239621 PMCID: PMC7688965 DOI: 10.1038/s41467-020-19783-w] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hop/Stip1/Sti1 is thought to be essential as a co-chaperone to facilitate substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Despite this proposed key function for protein folding and maturation, it is not essential in a number of eukaryotes and bacteria lack an ortholog. We set out to identify and to characterize its eukaryote-specific function. Human cell lines and the budding yeast with deletions of the Hop/Sti1 gene display reduced proteasome activity due to inefficient capping of the core particle with regulatory particles. Unexpectedly, knock-out cells are more proficient at preventing protein aggregation and at promoting protein refolding. Without the restraint by Hop, a more efficient folding activity of the prokaryote-like Hsp70-Hsp90 complex, which can also be demonstrated in vitro, compensates for the proteasomal defect and ensures the proteostatic equilibrium. Thus, cells may act on the level and/or activity of Hop to shift the proteostatic balance between folding and degradation. Hop, also known as Stip1 or Sti1, facilitates substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Characterization of proteostasis-related pathways in STIP1 knock-out cell lines reveals that in eukaryotes Stip1 modulates the balance between protein folding and degradation.
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Affiliation(s)
- Kaushik Bhattacharya
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland
| | - Lorenz Weidenauer
- Protein Analysis Facility, Center for Integrative Genomics, Université de Lausanne, 1015, Lausanne, Switzerland
| | - Tania Morán Luengo
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584, CH, Utrecht, The Netherlands.,Science for Life, Utrecht University, 3584, CH, Utrecht, The Netherlands
| | - Ellis C Pieters
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584, CH, Utrecht, The Netherlands.,Science for Life, Utrecht University, 3584, CH, Utrecht, The Netherlands
| | - Pablo C Echeverría
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland.,European Association for the Study of the Liver, 1203, Genève, Switzerland
| | - Lilia Bernasconi
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland
| | - Diana Wider
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland
| | - Yashar Sadian
- Bioimaging Center, Université de Genève, Sciences II, 1211, Genève 4, Switzerland
| | - Margreet B Koopman
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584, CH, Utrecht, The Netherlands.,Science for Life, Utrecht University, 3584, CH, Utrecht, The Netherlands
| | - Matthieu Villemin
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland
| | - Christoph Bauer
- Bioimaging Center, Université de Genève, Sciences II, 1211, Genève 4, Switzerland
| | - Stefan G D Rüdiger
- Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584, CH, Utrecht, The Netherlands.,Science for Life, Utrecht University, 3584, CH, Utrecht, The Netherlands
| | - Manfredo Quadroni
- Protein Analysis Facility, Center for Integrative Genomics, Université de Lausanne, 1015, Lausanne, Switzerland
| | - Didier Picard
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland.
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40
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Silva MC, Haggarty SJ. Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies. Int J Mol Sci 2020; 21:ijms21238948. [PMID: 33255694 PMCID: PMC7728099 DOI: 10.3390/ijms21238948] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/20/2020] [Accepted: 11/22/2020] [Indexed: 12/13/2022] Open
Abstract
Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer's disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., MAPT mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed.
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41
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Sarraf SA, Shah HV, Kanfer G, Pickrell AM, Holtzclaw LA, Ward ME, Youle RJ. Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain. Mol Cell 2020; 80:779-795.e10. [PMID: 33207181 DOI: 10.1016/j.molcel.2020.10.041] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 09/02/2020] [Accepted: 10/27/2020] [Indexed: 12/18/2022]
Abstract
Protein aggregates disrupt cellular homeostasis, causing toxicity linked to neurodegeneration. Selective autophagic elimination of aggregates is critical to protein quality control, but how aggregates are selectively targeted for degradation is unclear. We compared the requirements for autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in clearance of proteotoxic aggregates. Endogenous TAX1BP1 is recruited to and required for the clearance of stress-induced aggregates, whereas ectopic expression of TAX1BP1 increases clearance through autophagy, promoting viability of human induced pluripotent stem cell-derived neurons. In contrast, TAX1BP1 depletion sensitizes cells to several forms of aggregate-induced proteotoxicity. Furthermore, TAX1BP1 is more specifically expressed in the brain compared to other autophagy receptor proteins. In vivo, loss of TAX1BP1 results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains of young TAX1BP1 knockout mice. TAX1BP1 mediates clearance of a broad range of cytotoxic proteins indicating therapeutic potential in neurodegenerative diseases.
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Affiliation(s)
- Shireen A Sarraf
- Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Hetal V Shah
- Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD 20742, USA
| | - Gil Kanfer
- Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alicia M Pickrell
- School of Neuroscience, College of Science, Virginia Tech, Blacksburg, VA 24061, USA
| | - Lynne A Holtzclaw
- Microscopy and Imaging Core, Office of the Scientific Director, Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael E Ward
- Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard J Youle
- Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Program in Neuroscience and Cognitive Science, University of Maryland, College Park, MD 20742, USA.
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42
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Mitra P, Deshmukh AS, Choudhury C. Molecular chaperone function of stress inducible Hsp70 is critical for intracellular multiplication of Toxoplasma gondii. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1868:118898. [PMID: 33157166 DOI: 10.1016/j.bbamcr.2020.118898] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 11/27/2022]
Abstract
Intracellular pathogens like Toxoplasma gondii often target proteins and pathways critical for host cell survival and stress response. Molecular chaperones encoded by the evolutionary conserved Heat shock proteins (Hsps) maintain proteostasis and are vital to cell survival following exposure to any form of stress. A key protein of this family is Hsp70, an ATP-driven molecular chaperone, which is stress inducible and often indiscernible in normal cells. Role of this protein with respect to intracellular survival and multiplication of protozoan parasite like T. gondii remains to be examined. We find that T. gondii infection upregulates expression of host Hsp70. Hsp70 selective inhibitor 2-phenylethynesulfonamide (PES) attenuates intracellular T. gondii multiplication. Biotinylated PES confirms selective interaction of this small molecule inhibitor with Hsp70. We show that PES acts by disrupting Hsp70 chaperone function which leads to dysregulation of host autophagy. Silencing of host Hsp70 underscores its importance for intracellular multiplication of T. gondii, however, attenuation achieved using PES is not completely attributable to host Hsp70 indicating the presence of other intracellular targets of PES in infected host cells. We find that PES is also able to target T. gondii Hsp70 homologue which was shown using PES binding assay. Detailed molecular docking analysis substantiates PES targeting of TgHsp70 in addition to host Hsp70. While establishing the importance of protein quality control in infection, this study brings to the fore a unique opportunity of dual targeting of host and parasite Hsp70 demonstrating how structural conservation of these proteins may be exploited for therapeutic design.
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Affiliation(s)
- Pallabi Mitra
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India.
| | | | - Chinmayee Choudhury
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Research and Education, Chandigarh, India
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Adnan G, Rubikaite A, Khan M, Reber M, Suetterlin P, Hindges R, Drescher U. The GTPase Arl8B Plays a Principle Role in the Positioning of Interstitial Axon Branches by Spatially Controlling Autophagosome and Lysosome Location. J Neurosci 2020; 40:8103-8118. [PMID: 32917789 PMCID: PMC7574663 DOI: 10.1523/jneurosci.1759-19.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 07/13/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
Interstitial axon branching is an essential step during the establishment of neuronal connectivity. However, the exact mechanisms on how the number and position of branches are determined are still not fully understood. Here, we investigated the role of Arl8B, an adaptor molecule between lysosomes and kinesins. In chick retinal ganglion cells (RGCs), downregulation of Arl8B reduces axon branch density and shifts their location more proximally, while Arl8B overexpression leads to increased density and more distal positions of branches. These alterations correlate with changes in the location and density of lysosomes and autophagosomes along the axon shaft. Diminishing autophagy directly by knock-down of atg7, a key autophagy gene, reduces branch density, while induction of autophagy by rapamycin increases axon branching, indicating that autophagy plays a prominent role in axon branch formation. In vivo, local inactivation of autophagy in the retina using a mouse conditional knock-out approach disturbs retino-collicular map formation which is dependent on the formation of interstitial axon branches. These data suggest that Arl8B plays a principal role in the positioning of axon branches by spatially controlling autophagy, thus directly controlling formation of neural connectivity in the brain.SIGNIFICANCE STATEMENT The formation of interstitial axonal branches plays a prominent role in numerous places of the developing brain during neural circuit establishment. We show here that the GTPase Arl8B controls density and location of interstitial axon branches, and at the same time controls also density and location of the autophagy machinery. Upregulation or downregulation of autophagy in vitro promotes or inhibits axon branching. Local disruption of autophagy in vivo disturbs retino-collicular mapping. Our data suggest that Arl8B controls axon branching by controlling locally autophagy. This work is one of the first reports showing a role of autophagy during early neural circuit development and suggests that autophagy in general plays a much more prominent role during brain development than previously anticipated.
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Affiliation(s)
- Gee Adnan
- Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
| | - Aine Rubikaite
- Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
| | - Moqadisa Khan
- Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
| | - Michael Reber
- Krembil Research Institute, Toronto, Ontario M5T 0S8, Canada
| | - Philip Suetterlin
- Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
- Craniofacial Development and Stem Cell Biology, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom
| | - Robert Hindges
- Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, United Kingdom
| | - Uwe Drescher
- Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, United Kingdom
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44
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Lee C, Lamech L, Johns E, Overholtzer M. Selective Lysosome Membrane Turnover Is Induced by Nutrient Starvation. Dev Cell 2020; 55:289-297.e4. [PMID: 32916093 DOI: 10.1016/j.devcel.2020.08.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/02/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022]
Abstract
Lysosome function is essential for cellular homeostasis, but quality-control mechanisms that maintain healthy lysosomes remain poorly characterized. Here, we developed a method to measure lysosome turnover and use this to identify a selective mechanism of membrane degradation that involves lipidation of the autophagy protein LC3 onto lysosomal membranes and the formation of intraluminal vesicles through microautophagy. This mechanism is induced in response to metabolic stress resulting from glucose starvation or by treatment with pharmacological agents that induce osmotic stress on lysosomes. Cells lacking ATG5, an essential component of the LC3 lipidation machinery, show reduced ability to regulate lysosome size and degradative capacity in response to activation of this mechanism. These findings identify a selective mechanism of lysosome membrane turnover that is induced by stress and uncover a function for LC3 lipidation in regulating lysosome size and activity through microautophagy.
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Affiliation(s)
- Chan Lee
- Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA; BCMB Allied Program, Weill Cornell Medical College, New York, NY 10065, USA
| | - Lilian Lamech
- Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
| | - Eleanor Johns
- Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA; Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michael Overholtzer
- Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA; BCMB Allied Program, Weill Cornell Medical College, New York, NY 10065, USA; Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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45
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Xu W, Chen B, Ke D, Chen X. DUSP4 directly deubiquitinates and stabilizes Smad4 protein, promoting proliferation and metastasis of colorectal cancer cells. Aging (Albany NY) 2020; 12:17634-17646. [PMID: 32897241 PMCID: PMC7521518 DOI: 10.18632/aging.103823] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/06/2020] [Indexed: 01/24/2023]
Abstract
Colorectal cancer is a common health-threatening tumor within the gastrointestinal tract. The aim of this study was to test the biological role of DUSP4 in colorectal cancer cells. In our study, DUSP4 overexpression-treated HCT116 cells and DUSP4 knockdown-treated SW480 cells were selected to perform study. Quantitative real-time PCR test (qRT-PCR) and western blot were used to detect DUSP4 abundance in clinical tissues and six cell lines, as well as ubiquitin-related Smad4 degradation. Western blot, migration and invasion. were used to assess the relationships between DUSP4 and Smad4. Higher DUSP4 expression of functional significance was observed in colorectal cancer tissues and cells. The results showed that both treatments could affect the proliferation, colony formation, migration, invasion of tumor cells, and the expression of epithelial mesenchymal transformation (EMT)-associated biomarkers. Moreover, in colorectal cancer cells, DUSP4 could promote the Smad4 degradation by regulating ubiquitin-related Smad4 degradation, and promote the cell proliferation, migration and invasion by regulating Smad4 degradation via Smad4 gene. Meanwhile, DUSP4 can directly deubiquitinate and stabilize Smad4 protein, hence further promote proliferation and metastasis of colorectal cancer cells.
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Affiliation(s)
- Weifeng Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
| | - Beibei Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
| | - Dianshan Ke
- Department of Cell Biology, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Xiaobing Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
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46
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Zhang L, Afolabi LO, Wan X, Li Y, Chen L. Emerging Roles of Tripartite Motif-Containing Family Proteins (TRIMs) in Eliminating Misfolded Proteins. Front Cell Dev Biol 2020; 8:802. [PMID: 32984318 PMCID: PMC7479839 DOI: 10.3389/fcell.2020.00802] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
Protein quality control (PQC) is pivotal for eukaryotic cells to eliminate misfolded proteins and maintain cellular homeostasis. A decreased or increased capacity of PQC is associated with various diseases, e.g., neurodegenerative diseases and cancers. Recently, increasing evidences have suggested that tripartite motif-containing family proteins (TRIMs) are the key players in PQC regulation. Most TRIMs are E3 ubiquitin ligases, such as TRIM11/19/25, which, through the ubiquitination modifications, can contribute to effectively remove the cellular misfolded proteins or protein aggregates via the UPS pathway. In this review, we summarized the participation of TRIM members in misfolded protein elimination through distinct pathways, including the ubiquitin-proteasome system (UPS), autophagy system, and ER-associated degradation (ERAD).
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Affiliation(s)
- Litian Zhang
- Shenzhen Laboratory of Tumor Cell Biology, Center for Antibody Drug Development, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.,Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lukman O Afolabi
- Shenzhen Laboratory of Tumor Cell Biology, Center for Antibody Drug Development, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Xiaochun Wan
- Shenzhen Laboratory of Tumor Cell Biology, Center for Antibody Drug Development, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yang Li
- Shenzhen Laboratory of Tumor Cell Biology, Center for Antibody Drug Development, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Liang Chen
- Shenzhen Laboratory of Tumor Cell Biology, Center for Antibody Drug Development, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Abstract
Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.
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Affiliation(s)
- Thorsten Hoppe
- Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne 50931, Germany and
| | - Ehud Cohen
- Department of Biochemistry and Molecular Biology, the Institute for Medical Research Israel-Canada (IMRIC), the Hebrew University School of Medicine, Jerusalem 91120, Israel
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48
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Xu W, Chen B, Ke D, Chen X. TRIM29 mediates lung squamous cell carcinoma cell metastasis by regulating autophagic degradation of E-cadherin. Aging (Albany NY) 2020; 12:13488-13501. [PMID: 32640423 PMCID: PMC7377877 DOI: 10.18632/aging.103451] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 05/01/2020] [Indexed: 01/09/2023]
Abstract
Lung squamous cell carcinoma (LSCC) is the most common histological type of primary lung cancer. In this study, we had tested the biological role of TRIM29 in LSCC cells. TRIM29 abundance, the relationships between TRIM29 and E-cadherin and autophagy degradation related proteins in clinical tissues and six cell lines were studied with quantitative real-time PCR test (qRT-PCR) and western blot. TRIM29 overexpression treated HTB-182 cells and knockdown treated NCL-H1915 cells was used for studying cell proliferation, colony formation, migration, invasion, and the expression of epithelial mesenchymal transformation (EMT) associated biomarkers. The relationships between TRIM29 and BECN1 were investigated with western blot. TRIM29 was profoundly overexpressed in LSCC tissues and cells compared with human normal bronchial epithelial cells (HNBE). High TRIM29 expression was closely related to overall survival (OS). TRIM29 overexpression and knockdown affected LSCC activity and the expression of EMT associated biomarkers. TRIM29 can regulate the degradation of E-cadherin and autophagy of LSCC through BECN1 gene, and promote autophagy in HTB-182 and NCL-H1915 cells. Our results revealed that TRIM29 could promote the proliferation, migration, and invasion of LSCC via E-cadherin autophagy degradation. The results are useful for further study in LSCC.
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Affiliation(s)
- Weifeng Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
| | - Beibei Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
| | - Dianshan Ke
- Department of Cell Biology, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Xiaobing Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, P.R. China
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49
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Yamashima T, Ota T, Mizukoshi E, Nakamura H, Yamamoto Y, Kikuchi M, Yamashita T, Kaneko S. Intake of ω-6 Polyunsaturated Fatty Acid-Rich Vegetable Oils and Risk of Lifestyle Diseases. Adv Nutr 2020; 11:1489-1509. [PMID: 32623461 PMCID: PMC7666899 DOI: 10.1093/advances/nmaa072] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/30/2019] [Accepted: 05/26/2020] [Indexed: 12/28/2022] Open
Abstract
Although excessive consumption of deep-fried foods is regarded as 1 of the most important epidemiological factors of lifestyle diseases such as Alzheimer's disease, type 2 diabetes, and obesity, the exact mechanism remains unknown. This review aims to discuss whether heated cooking oil-derived peroxidation products cause cell degeneration/death for the occurrence of lifestyle diseases. Deep-fried foods cooked in ω-6 PUFA-rich vegetable oils such as rapeseed (canola), soybean, sunflower, and corn oils, already contain or intrinsically generate "hydroxynonenal" by peroxidation. As demonstrated previously, hydroxynonenal promotes carbonylation of heat-shock protein 70.1 (Hsp70.1), with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. Until now, the implication of lysosomal/autophagy failure due to the daily consumption of ω-6 PUFA-rich vegetable oils in the progression of cell degeneration/death has not been reported. Since the "calpain-cathepsin hypothesis" was formulated as a cause of ischemic neuronal death in 1998, its relevance to Alzheimer's neuronal death has been suggested with particular attention to hydroxynonenal. However, its relevance to cell death of the hypothalamus, liver, and pancreas, especially related to appetite/energy control, is unknown. The hypothalamus senses information from both adipocyte-derived leptin and circulating free fatty acids. Concentrations of circulating fatty acid and its oxidized form, especially hydroxynonenal, are increased in obese and/or aged subjects. As overactivation of the fatty acid receptor G-protein coupled receptor 40 (GPR40) in response to excessive or oxidized fatty acids in these subjects may lead to the disruption of Ca2+ homeostasis, it should be evaluated whether GPR40 overactivation contributes to diverse cell death. Here, we describe the molecular implication of ω-6 PUFA-rich vegetable oil-derived hydroxynonenal in lysosomal destabilization leading to cell death. By oxidizing Hsp70.1, both the dietary PUFA- (exogenous) and the membrane phospholipid- (intrinsic) peroxidation product "hydroxynonenal," when combined, may play crucial roles in the occurrence of diverse lifestyle diseases including Alzheimer's disease.
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Affiliation(s)
| | | | | | | | - Yasuhiko Yamamoto
- Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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50
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Wen X, An P, Li H, Zhou Z, Sun Y, Wang J, Ma L, Lu B. Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS. Neurosci Bull 2020; 36:1414-1428. [PMID: 32500377 DOI: 10.1007/s12264-020-00518-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 03/21/2020] [Indexed: 12/21/2022] Open
Abstract
Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome-lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.
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Affiliation(s)
- Xue Wen
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Ping An
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Hexuan Li
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Zijian Zhou
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Yimin Sun
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Jian Wang
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China.
| | - Lixiang Ma
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
| | - Boxun Lu
- Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, 200438, China.
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