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Xu Q, Liu D, Zhu LQ, Su Y, Huang HZ. Long non-coding RNAs as key regulators of neurodegenerative protein aggregation. Alzheimers Dement 2025; 21:e14498. [PMID: 39936251 DOI: 10.1002/alz.14498] [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: 09/12/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 02/13/2025]
Abstract
The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated in the pathological processes of different NDDs, the process of protein misfolding and aggregation remains notably similar across various conditions. Specifically, proteins undergo misfolding into beta-folded (β-folded) conformation, resulting in the formation of insoluble amyloid proteins. Despite advancements in comprehending protein aggregation, certain facets of this intricate process remain incompletely elucidated. In recent years, the concept that long non-coding RNAs (lncRNAs) contribute to protein aggregation has gained recognition. LncRNAs influence the formation of protein aggregates by facilitating protein overexpression through the regulation of gene transcription and translation, inhibiting protein degradation via lysosomal and autophagic pathways, and targeting aberrant modifications and phase transitions of proteins. A better understanding of the relationship between lncRNAs and aberrant protein aggregation is an important step in dissecting the underlying molecular mechanisms and will contribute to the discovery of new therapeutic targets and strategies. HIGHLIGHTS: NDDs are marked by protein misfolding, aggregation, and accumulation, leading to cellular dysfunction and loss of synaptic function. Despite different proteins being involved in various NDDs, the process of misfolding into β-folded conformations and forming insoluble amyloid proteins is consistent across conditions. The role of lncRNAs in protein aggregation has gained attention, as they regulate gene transcription and translation, inhibit protein degradation, and target aberrant protein modifications. Understanding the link between lncRNAs and protein aggregation is crucial for uncovering molecular mechanisms and developing new therapeutic targets.
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Affiliation(s)
- Qi Xu
- Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Liu
- Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ling-Qiang Zhu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ying Su
- Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - He-Zhou Huang
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Anesthesiology Department, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
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Jiménez-Ramírez IA, Castaño E. Non-coding RNAs in the pathogenesis of Alzheimer's disease: β-amyloid aggregation, Tau phosphorylation and neuroinflammation. Mol Biol Rep 2025; 52:183. [PMID: 39890684 DOI: 10.1007/s11033-025-10284-x] [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: 12/09/2024] [Accepted: 01/21/2025] [Indexed: 02/03/2025]
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder primarily affecting individuals aged 65 and older, characterized by cognitive decline and diminished quality of life. The molecular hallmarks of AD include extracellular β-amyloid plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and chronic neuroinflammation. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as potential therapeutic targets due to their regulatory roles in AD pathogenesis. For example, miR-124 has been shown to modulate Aβ levels, while lncRNAs such as BACE1-AS regulate the expression of BACE1, a crucial enzyme in Aβ production. Transcriptomic studies of AD patients have revealed dysregulation of ncRNA expression, further supporting their involvement in disease progression. This review examines the regulatory functions of ncRNAs in AD, focusing on their impact on Aβ, tau hyperphosphorylation, and neuroinflammation. Additionally, we discuss the emerging role of ncRNAs in liquid-liquid phase separation and the formation of protein aggregates, key processes contributing to AD pathology.
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Affiliation(s)
- Irma A Jiménez-Ramírez
- Centro de Investigación Científica de Yucatán, Unidad de Biología Integrativa, Calle 43 No. 130 X 32 y 34. Col. Chuburná de Hidalgo, 97205, Mérida, Yucatán, México
| | - Enrique Castaño
- Centro de Investigación Científica de Yucatán, Unidad de Biología Integrativa, Calle 43 No. 130 X 32 y 34. Col. Chuburná de Hidalgo, 97205, Mérida, Yucatán, México.
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3
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Chadourne M, Griffith C, Xu X, Brennan E, Vera O, Mecozzi N, Wang K, Jaeger AM, Karreth FA. CDH3-AS1 antisense RNA enhances P-cadherin translation and acts as a tumor suppressor in melanoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.26.630428. [PMID: 39764055 PMCID: PMC11703152 DOI: 10.1101/2024.12.26.630428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Thousands of regulatory noncoding RNAs (ncRNAs) have been annotated; however, their functions in gene regulation and contributions to cancer formation remain poorly understood. To gain a better understanding of the influence of ncRNAs on gene regulation during melanoma progression, we mapped the landscape of ncRNAs in melanocytes and melanoma cells. Nearly half of deregulated genes in melanoma are ncRNAs, with antisense RNAs (asRNAs) comprising a large portion of deregulated ncRNAs. CDH3-AS1, the most significantly downregulated asRNA, overlaps the CDH3 gene, which encodes P-cadherin, a transmembrane glycoprotein involved in cell adhesion that was also reduced in melanoma. Overexpression of CDH3-AS1 increased cell aggregation and reduced xenograft tumor growth, mimicking the tumor-suppressive effects of CDH3. CDH3-AS1 interacted with CDH3 mRNA and enhanced P-cadherin protein levels. Interestingly, secondary structures at the CDH3 5' end regulated P-cadherin translation, and ribosome profiling revealed that CDH3-AS1 promotes ribosome occupancy at the CDH3 mRNA. Notably, ribosome occupancy was generally increased in mRNAs having cognate asRNA that are complementary to the 5'UTR. Taken together, this study revealed the CDH3-AS1-mediated enhancement of P-cadherin translation, underscoring the broader potential of asRNAs as regulators of protein-coding genes and their role in diseases like melanoma.
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Affiliation(s)
- Manon Chadourne
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Crystal Griffith
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Xiaonan Xu
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Emily Brennan
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Olga Vera
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Nicol Mecozzi
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
- Cancer Biology PhD Program, University of South Florida, Tampa, FL 33612, USA
| | - Kaizhen Wang
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
- Cancer Biology PhD Program, University of South Florida, Tampa, FL 33612, USA
| | - Alex M. Jaeger
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
| | - Florian A. Karreth
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
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Wu X, Xia P, Yang L, Lu C, Lu Z. The roles of long non-coding RNAs in Alzheimer's disease diagnosis, treatment, and their involvement in Alzheimer's disease immune responses. Noncoding RNA Res 2024; 9:659-666. [PMID: 38577023 PMCID: PMC10987299 DOI: 10.1016/j.ncrna.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 02/27/2024] [Accepted: 03/16/2024] [Indexed: 04/06/2024] Open
Abstract
Alzheimer's disease (AD) is the most frequent type of dementia, presenting a substantial danger to the health and well-being of the aged population. It has arisen as a significant public health problem with considerable socioeconomic repercussions. Unfortunately, no effective treatments or diagnostic tools are available for Alzheimer's disease. Despite substantial studies on the pathophysiology of Alzheimer's, the molecular pathways underpinning its development remain poorly understood. Long non-coding RNAs (lncRNAs) vary in size from 200 nucleotides to over 100 kilobytes and have been found to play critical roles in various vital biological processes that play critical in developing Alzheimer's disease. This review intends to examine the functions of long non-coding RNAs in diagnosing and treating Alzheimer's disease and their participation in immunological responses associated with AD.
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Affiliation(s)
- Xiaoben Wu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Pengcheng Xia
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Lei Yang
- Department of Medical Engineering, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chao Lu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhiming Lu
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Hernández-Contreras KA, Martínez-Díaz JA, Hernández-Aguilar ME, Herrera-Covarrubias D, Rojas-Durán F, Chi-Castañeda LD, García-Hernández LI, Aranda-Abreu GE. Alterations of mRNAs and Non-coding RNAs Associated with Neuroinflammation in Alzheimer's Disease. Mol Neurobiol 2024; 61:5826-5840. [PMID: 38236345 DOI: 10.1007/s12035-023-03908-5] [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: 04/12/2023] [Accepted: 12/27/2023] [Indexed: 01/19/2024]
Abstract
Alzheimer's disease is a neurodegenerative pathology whose pathognomonic hallmarks are increased generation of β-amyloid (Aβ) peptide, production of hyperphosphorylated (pTau), and neuroinflammation. The last is an alteration closely related to the progression of AD and although it is present in multiple neurodegenerative diseases, the pathophysiological events that characterize neuroinflammatory processes vary depending on the disease. In this article, we focus on mRNA and non-coding RNA alterations as part of the pathophysiological events characteristic of neuroinflammation in AD and the influence of these alterations on the course of the disease through interaction with multiple RNAs related to the generation of Aβ, pTau, and neuroinflammation itself.
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Affiliation(s)
- Karla Aketzalli Hernández-Contreras
- Doctorado en Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - Jorge Antonio Martínez-Díaz
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - María Elena Hernández-Aguilar
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - Deissy Herrera-Covarrubias
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - Fausto Rojas-Durán
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - Lizbeth Donají Chi-Castañeda
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - Luis Isauro García-Hernández
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México
| | - Gonzalo Emiliano Aranda-Abreu
- Instituto de Investigaciones Cerebrales/Universidad Veracruzana, Av. Luis Castelazo Ayala S/N, Carr. Xalapa-Veracruz, Km 3.5, C.P. 91190, Xalapa, Veracruz, México.
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Filomena E, Picardi E, Tullo A, Pesole G, D’Erchia AM. Identification of deregulated lncRNAs in Alzheimer's disease: an integrated gene co-expression network analysis of hippocampus and fusiform gyrus RNA-seq datasets. Front Aging Neurosci 2024; 16:1437278. [PMID: 39086756 PMCID: PMC11288953 DOI: 10.3389/fnagi.2024.1437278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/08/2024] [Indexed: 08/02/2024] Open
Abstract
Introduction The deregulation of lncRNAs expression has been associated with neuronal damage in Alzheimer's disease (AD), but how or whether they can influence its onset is still unknown. We investigated 2 RNA-seq datasets consisting, respectively, of the hippocampal and fusiform gyrus transcriptomic profile of AD patients, matched with non-demented controls. Methods We performed a differential expression analysis, a gene correlation network analysis (WGCNA) and a pathway enrichment analysis of two RNA-seq datasets. Results We found deregulated lncRNAs in common between hippocampus and fusiform gyrus and deregulated gene groups associated to functional pathways related to neurotransmission and memory consolidation. lncRNAs, co-expressed with known AD-related coding genes, were identified from the prioritized modules of both brain regions. Discussion We found common deregulated lncRNAs in the AD hippocampus and fusiform gyrus, that could be considered common signatures of AD pathogenesis, providing an important source of information for understanding the molecular changes of AD.
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Affiliation(s)
- Ermes Filomena
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Ernesto Picardi
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Graziano Pesole
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
| | - Anna Maria D’Erchia
- Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy
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Adeoye T, Shah SI, Ullah G. Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer's Disease. Aging Dis 2024:AD.2024.0429. [PMID: 38913039 DOI: 10.14336/ad.2024.0429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/12/2024] [Indexed: 06/25/2024] Open
Abstract
Alzheimer's disease (AD) manifests as a complex systems pathology with intricate interplay among various genes and biological processes. Traditional differential gene expression (DEG) analysis, while commonly employed to characterize AD-driven perturbations, does not sufficiently capture the full spectrum of underlying biological processes. Utilizing single-nucleus RNA-sequencing data from postmortem brain samples across key regions-middle temporal gyrus, superior frontal gyrus, and entorhinal cortex-we provide a comprehensive systematic analysis of disrupted processes in AD. We go beyond the DEG-centric analysis by integrating pathway activity analysis with weighted gene co-expression patterns to comprehensively map gene interconnectivity, identifying region- and cell-type-specific drivers of biological processes associated with AD. Our analysis reveals profound modular heterogeneity in neurons and glia as well as extensive AD-related functional disruptions. Co-expression networks highlighted the extended involvement of astrocytes and microglia in biological processes beyond neuroinflammation, such as calcium homeostasis, glutamate regulation, lipid metabolism, vesicle-mediated transport, and TOR signaling. We find limited representation of DEGs within dysregulated pathways across neurons and glial cells, suggesting that differential gene expression alone may not adequately represent the disease complexity. Further dissection of inferred gene modules revealed distinct dynamics of hub DEGs in neurons versus glia, suggesting that DEGs exert more impact on neurons compared to glial cells in driving modular dysregulations underlying perturbed biological processes. Interestingly, we observe an overall downregulation of astrocyte and microglia modules across all brain regions in AD, indicating a prevailing trend of functional repression in glial cells across these regions. Notable genes from the CALM and HSP90 families emerged as hub genes across neuronal modules in all brain regions, suggesting conserved roles as drivers of synaptic dysfunction in AD. Our findings demonstrate the importance of an integrated, systems-oriented approach combining pathway and network analysis to comprehensively understand the cell-type-specific roles of genes in AD-related biological processes.
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Zhao N, Wang J, Huang S, Zhang J, Bao J, Ni H, Gao X, Zhang C. The landscape of programmed cell death-related lncRNAs in Alzheimer's disease and Parkinson's disease. Apoptosis 2024:10.1007/s10495-024-01984-z. [PMID: 38853201 DOI: 10.1007/s10495-024-01984-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2024] [Indexed: 06/11/2024]
Abstract
This study delivers a thorough analysis of long non-coding RNAs (lncRNAs) in regulating programmed cell death (PCD), vital for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). We propose a new framework PCDLnc, and identified 20 significant lncRNAs, including HEIH, SNHG15, and SNHG5, associated with PCD gene sets, which were known for roles in proliferation and apoptosis in neurodegenerative diseases. By using GREAT software, we identified regulatory functions of top lncRNAs in different neurodegenerative diseases. Moreover, lncRNAs cis-regulated mRNAs linked to neurodegeneration, including JAK2, AKT1, EGFR, CDC42, SNCA, and ADIPOQ, highlighting their therapeutic potential in neurodegenerative diseases. A further exploration into the differential expression of mRNA identified by PCDLnc revealed a role in apoptosis, ferroptosis and autophagy. Additionally, protein-protein interaction (PPI) network analysis exposed abnormal interactions among key genes, despite their consistent expression levels between disease and normal samples. The randomforest model effectively distinguished between disease samples, indicating a high level of accuracy. Shared gene subsets in AD and PD might serve as potential biomarkers, along with disease-specific gene sets. Besides, we also found the strong relationship between AD and immune infiltration. This research highlights the role of lncRNAs and their associated genes in PCD in neurodegenerative diseases, offering potential therapeutic targets and diagnostic markers for future study and clinical application.
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Affiliation(s)
- Ning Zhao
- College of Computer and Control Engineering, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Junyi Wang
- College of Computer and Control Engineering, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Shan Huang
- The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China
| | - Jingyu Zhang
- The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China
| | - Jin Bao
- College of Computer and Control Engineering, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Haisen Ni
- College of Computer and Control Engineering, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Xinhang Gao
- College of Computer and Control Engineering, Northeast Forestry University, Harbin, Heilongjiang, China
| | - Chunlong Zhang
- College of Computer and Control Engineering, Northeast Forestry University, Harbin, Heilongjiang, China.
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Liu H, Li J, Wang X, Luo S, Luo D, Ge W, Ma C. Profiling of long non-coding RNAs in hippocampal-entorhinal system subfields: impact of RN7SL1 on neuroimmune response modulation in Alzheimer's disease. J Neuroinflammation 2024; 21:84. [PMID: 38582873 PMCID: PMC10999094 DOI: 10.1186/s12974-024-03083-x] [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: 01/02/2024] [Accepted: 03/30/2024] [Indexed: 04/08/2024] Open
Abstract
Alzheimer's disease (AD) is recognized as the predominant cause of dementia, and neuroimmune processes play a pivotal role in its pathological progression. The involvement of long non-coding RNAs (lncRNAs) in AD has attracted widespread attention. Herein, transcriptomic analysis of 262 unique samples extracted from five hippocampal-entorhinal system subfields of individuals with AD pathology and without AD pathology revealed distinctive lncRNA expression profiles. Through differential expression and coexpression analyses, we identified 16 pivotal lncRNAs. Notably, RN7SL1 knockdown significantly modulated microglial responses upon oligomeric amyloid-β stimulation, resulting in a considerable decrease in proinflammatory cytokine production and subsequent neuronal damage. These findings highlight RN7SL1 as an essential neuroimmune-related lncRNA that could serve as a prospective target for AD diagnosis and treatment.
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Affiliation(s)
- Hanyou Liu
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Jingying Li
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Xue Wang
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Shiqi Luo
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Dan Luo
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
| | - Wei Ge
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
| | - Chao Ma
- Department of Human Anatomy, Histology and Embryology, Neuroscience Center, National Human Brain Bank for Development and Function, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
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Adeoye T, Shah SI, Ullah G. Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer's Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.15.585267. [PMID: 38559218 PMCID: PMC10980062 DOI: 10.1101/2024.03.15.585267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Alzheimer's disease (AD) manifests as a complex systems pathology with intricate interplay among various genes and biological processes. Traditional differential gene expression (DEG) analysis, while commonly employed to characterize AD-driven perturbations, does not sufficiently capture the full spectrum of underlying biological processes. Utilizing single-nucleus RNA-sequencing data from postmortem brain samples across key regions-middle temporal gyrus, superior frontal gyrus, and entorhinal cortex-we provide a comprehensive systematic analysis of disrupted processes in AD. We go beyond the DEG-centric analysis by integrating pathway activity analysis with weighted gene co-expression patterns to comprehensively map gene interconnectivity, identifying region- and cell-type-specific drivers of biological processes associated with AD. Our analysis reveals profound modular heterogeneity in neurons and glia as well as extensive AD-related functional disruptions. Co-expression networks highlighted the extended involvement of astrocytes and microglia in biological processes beyond neuroinflammation, such as calcium homeostasis, glutamate regulation, lipid metabolism, vesicle-mediated transport, and TOR signaling. We find limited representation of DEGs within dysregulated pathways across neurons and glial cells, indicating that differential gene expression alone may not adequately represent the disease complexity. Further dissection of inferred gene modules revealed distinct dynamics of hub DEGs in neurons versus glia, highlighting the differential impact of DEGs on neurons compared to glial cells in driving modular dysregulations underlying perturbed biological processes. Interestingly, we note an overall downregulation of both astrocyte and microglia modules in AD across all brain regions, suggesting a prevailing trend of functional repression in glial cells across these regions. Notable genes, including those of the CALM and HSP90 family genes emerged as hub genes across neuronal modules in all brain regions, indicating conserved roles as drivers of synaptic dysfunction in AD. Our findings demonstrate the importance of an integrated, systems-oriented approach combining pathway and network analysis for a comprehensive understanding of the cell-type-specific roles of genes in AD-related biological processes.
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Affiliation(s)
- Temitope Adeoye
- Department of Physics, University of South Florida, Tampa, FL 33620
| | - Syed I Shah
- Department of Physics, University of South Florida, Tampa, FL 33620
| | - Ghanim Ullah
- Department of Physics, University of South Florida, Tampa, FL 33620
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11
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Gong F, Wei Y. LncRNA PVT1 promotes neuroinflammation after intracerebral hemorrhage by regulating the miR-128-3p/TXNIP axis. Int J Neurosci 2024:1-15. [PMID: 38294729 DOI: 10.1080/00207454.2024.2312998] [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: 10/20/2023] [Accepted: 01/27/2024] [Indexed: 02/01/2024]
Abstract
OBJECTIVE Intracerebral hemorrhage (ICH) has significant morbidity and mortality. TXNIP and the competing endogenous RNA (ceRNA) regulatory mechanism involved in long non-coding RNA (lncRNA) play roles in ICH. We probed the upstream microRNAs (miRNAs)/lncRNAs that regulated TXNIP expression in the ceRNA mechanism. METHODS ICH mouse model was established, and ICH secondary injury was simulated in BV2 microglia by hemin treatment. TXNIP was silenced 48 h before ICH modeling. The ICH mouse brain water content (BWC) and brain lesion volume after ICH were recorded. Neuronal apoptosis and neurological deficits were evaluated by double staining of NeuN and TUNEL/modified Garcia/corner turn/forelimb placement tests. Iba1 + microglia number and tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/IL-10/TXNIP/PVT1/miR-128-3p levels were assessed by immunohistochemistry, Western blot, ELISA, and RT-qPCR. Cell viability/death of BV2 cells conditioned medium-treated neuron HT22 cells were assessed by CCK-8/LDH assays. miRNA that had a targeted binding relationship with TXNIP was screened. The targeted bindings of miR-128-3p to TXNIP/PVT1 to miR-128-3p were verified by dual-luciferase reporter gene assay. RESULTS TXNIP knockdown reduced post-ICH microglial activation/release of pro-inflammatory factors/brain edema/brain lesion volume/neurological deficits in mice and increased releases of anti-inflammatory factors. TXNIP/PVT1 knockdown inhibited hemin-induced inflammatory responses in BV2 cells and protected in vitro co-cultured HT22 cells. PVT1 was a sponge of miR-128-3p to repress TXNIP expression. miR-128-3p knockdown diminished PVT1 knockdown-inhibited hemin-induced BV2 cell inflammatory responses/neurotoxicity. CONCLUSIONS PVT1 silencing reduced hemin-induced neuroinflammation and had a protective effect on neurons by increasing the targeted inhibition of TXNIP by miR-128-3p.
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Affiliation(s)
- Fanyong Gong
- Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yiting Wei
- Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
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Saleh O, Albakri K, Altiti A, Abutair I, Shalan S, Mohd OB, Negida A, Mushtaq G, Kamal MA. The Role of Non-coding RNAs in Alzheimer's Disease: Pathogenesis, Novel Biomarkers, and Potential Therapeutic Targets. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:731-745. [PMID: 37211844 DOI: 10.2174/1871527322666230519113201] [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: 12/02/2022] [Revised: 03/24/2023] [Accepted: 03/29/2023] [Indexed: 05/23/2023]
Abstract
Long non-coding RNAs (IncRNAs) are regulatory RNA transcripts that have recently been associated with the onset of many neurodegenerative illnesses, including Alzheimer's disease (AD). Several IncRNAs have been found to be associated with AD pathophysiology, each with a distinct mechanism. In this review, we focused on the role of IncRNAs in the pathogenesis of AD and their potential as novel biomarkers and therapeutic targets. Searching for relevant articles was done using the PubMed and Cochrane library databases. Studies had to be published in full text in English in order to be considered. Some IncRNAs were found to be upregulated, while others were downregulated. Dysregulation of IncRNAs expression may contribute to AD pathogenesis. Their effects manifest as the synthesis of beta-amyloid (Aβ) plaques increases, thereby altering neuronal plasticity, inducing inflammation, and promoting apoptosis. Despite the need for more investigations, IncRNAs could potentially increase the sensitivity of early detection of AD. Until now, there has been no effective treatment for AD. Hence, InRNAs are promising molecules and may serve as potential therapeutic targets. Although several dysregulated AD-associated lncRNAs have been discovered, the functional characterization of most lncRNAs is still lacking.
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Affiliation(s)
- Othman Saleh
- Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Khaled Albakri
- Faculty of Medicine, The Hashemite University, Zarqa, Jordan
- Medical Research Group of Egypt, Cairo, Egypt
| | | | - Iser Abutair
- Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | - Suhaib Shalan
- Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | | | - Ahmed Negida
- Medical Research Group of Egypt, Cairo, Egypt
- Department of Global Health and Social Medicine, Harvard Medical School, 641 Huntington Ave, Boston, MA, 02115, USA
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
- Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Gohar Mushtaq
- Center for Scientific Research, Faculty of Medicine, Idlib University, Idlib, Syria
| | - Mohammad A Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Sichuan, China
- King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia 1216, Bangladesh
- Enzymoics, 7 Peterlee place, Hebersham, NSW 2770, Novel Global Community Educational Foundation, Hebersham, Australia
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13
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Adiga D, Eswaran S, Srinath S, Khan NG, Kumar D, Kabekkodu SP. Noncoding RNAs in Alzheimer's Disease: Overview of Functional and Therapeutic Significance. Curr Top Med Chem 2024; 24:1615-1634. [PMID: 38616763 DOI: 10.2174/0115680266293212240405042540] [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: 11/16/2023] [Revised: 02/29/2024] [Accepted: 03/07/2024] [Indexed: 04/16/2024]
Abstract
Alzheimer's disease (AD) is a multifactorial disorder resulting from the complex interaction between genetic, epigenetic, and environmental factors. It represents an impending epidemic and lacks effective pharmacological interventions. The emergence of high throughput sequencing techniques and comprehensive genome evaluation has uncovered a diverse spectrum of noncoding RNA (ncRNA) families. ncRNAs are the critical modulators of an eclectic array of biological processes and are now transpiring as imperative players in diagnosing and treating various diseases, including neurodegenerative disorders. Several ncRNAs are explicitly augmented in the brain, wherein they potentially regulate cognitive abilities and other functions of the central nervous system. Growing evidence suggests the substantial role of ncRNAs as modulators of tau phosphorylation, Aβ production, neuroinflammation, and neuronal survival. It indicates their therapeutic relevance as a biomarker and druggable targets against AD. The current review summarizes the existing literature on the functional significance of ncRNAs in AD pathogenesis and its imminent implications in clinics.
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Affiliation(s)
- Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, Karnataka, India
| | - Sangavi Eswaran
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, Karnataka, India
| | - Sriharikrishnaa Srinath
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, Karnataka, India
| | - Nadeem G Khan
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, Karnataka, India
| | - Dileep Kumar
- Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Erandwane, Pune, 411038, Maharashtra, India
- Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California Davis, One Shields Avenue, Davis, CA95616, USA
| | - Shama P Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, 576104, Karnataka, India
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Sundram S, Dhiman N, Malviya R, Awasthi R. Non-coding RNAs in Regulation of Protein Aggregation and Clearance Pathways: Current Perspectives Towards Alzheimer's Research and Therapy. Curr Gene Ther 2024; 24:8-16. [PMID: 37519207 DOI: 10.2174/1566523223666230731093030] [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: 09/21/2022] [Revised: 05/07/2023] [Accepted: 07/04/2023] [Indexed: 08/01/2023]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 45.0 million people worldwide and ranking as the fifth leading cause of mortality. AD is identified by neurofibrillary tangles (NFTs), which include abnormally phosphorylated tau-protein and amyloid protein (amyloid plaques). Peptide dysregulation is caused by an imbalance between the production and clearance of the amyloid-beta (Aβ) and NFT. AD begins to develop when these peptides are not cleared from the body. As a result, understanding the processes that control both normal and pathological protein recycling in neuronal cells is critical. Insufficient Aβ and NFT clearance are important factors in the development of AD. Autophagy, lysosomal dysfunction, and ubiquitin-proteasome dysfunction have potential roles in the pathogenesis of many neurodegenerative disorders, particularly in AD. Modulation of these pathways may provide a novel treatment strategy for AD. Non-coding RNAs (ncRNAs) have recently emerged as important biological regulators, with particular relevance to the emergence and development of neurodegenerative disorders such as AD. ncRNAs can be used as potential therapeutic targets and diagnostic biomarkers due to their critical regulatory functions in several biological processes involved in disease development, such as the aggregation and accumulation of Aβ and NFT. It is evident that ncRNAs play a role in the pathophysiology of AD. In this communication, we explored the link between ncRNAs and AD and their regulatory mechanisms that may help in finding new therapeutic targets and AD medications.
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Affiliation(s)
- Sonali Sundram
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, India
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Neerupma Dhiman
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, India
| | - Rajendra Awasthi
- Department of Pharmaceutical Sciences, School of Health Sciences & Technology, UPES University, Dehradun, Uttarakhand, India
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15
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Tang L, Wang Y, Xiang J, Yang D, Zhang Y, Xiang Q, Li J. lncRNA and circRNA expression profiles in the hippocampus of Aβ 25‑35‑induced AD mice treated with Tripterygium glycoside. Exp Ther Med 2023; 26:426. [PMID: 37602300 PMCID: PMC10433443 DOI: 10.3892/etm.2023.12125] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 03/15/2023] [Indexed: 08/22/2023] Open
Abstract
Tripterygium glycosides (TG) have been reported to ameliorate Alzheimer's disease (AD), although the mechanism involved remains to be determined. In the present study, the lncRNA and circRNA expression profiles of an AD mouse model treated with TG were assessed using microarrays. lncRNAs, mRNAs, and circRNAs in the hippocampi of 3 AD+normal saline (NS) mice and 3 AD+TG mice were detected using microarrays. The most differentially expressed lncRNAs, mRNAs, and circRNAs were screened between the AD+NS and AD+TG groups. The differentially expressed lncRNAs and circRNAs were analyzed using GO enrichment and KEGG analyses. Co-expression analysis of lncRNAs, circRNAs, and mRNAs was performed by calculating the correlation coefficients. Protein-protein interaction (PPI) network analysis was performed on mRNAs using STRING. The lncRNA-target-transcription factor (TF) network was analyzed using the Network software. In total, 661 lncRNAs, 64 circRNAs, and 503 mRNAs were found to be differentially expressed in AD mice treated with TG. Pou4f1, Egr2, Mag, and Nr4a1 were the hub genes in the PPI network. The KEGG results showed that the mRNAs that were co-expressed with lncRNAs were enriched in the TNF, PI3K-Akt, and Wnt signaling pathways. LncRNA-target-TF network analysis indicated that TFs, including Cebpa, Zic2, and Rxra, were the most likely to regulate the detected lncRNAs. The circRNA-miRNA interaction network indicated that 275 miRNAs may bind to the 64 circRNAs. In conclusion, these findings provide a novel perspective on AD pathogenesis, and the detected lncRNAs, mRNAs, and circRNAs may serve as novel therapeutic targets for the management of AD.
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Affiliation(s)
- Liang Tang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Department of Basic Biology, Wuzhou Medical College, Wuzhou, Guangxi Zhuang 543000, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Yan Wang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Department of Basic Biology, Wuzhou Medical College, Wuzhou, Guangxi Zhuang 543000, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Ju Xiang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Dawei Yang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Yan Zhang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- School of Computer Science and Engineering, Central South University, Changsha, Hunan 410083, P.R. China
| | - Qin Xiang
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
| | - Jianming Li
- Department of Basic Biology, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, Hunan 410219, P.R. China
- The Hunan Provincial University Key Laboratory of The Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, Hunan 410219, P.R. China
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16
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Cheng Y, Zhou X, Zou T, Zhang L, Li L, Yang C, Ma L. Plasma long non-coding RNAs ASMTL-AS1, AP001363.1, AC005730.3 and AL133415.1 as a potential biomarker for Alzheimer's disease. Neurol Res 2023; 45:804-817. [PMID: 37486018 DOI: 10.1080/01616412.2023.2203616] [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: 11/01/2022] [Accepted: 04/12/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) play critical role in the pathogenesis of neurodegenerative diseases. Human plasma contains lncRNAs that are present in the blood, and their disease-specific profile has been considered a potential biomarker in some diseases. METHODS This study reports screening of the plasma levels of lncRNAs between Alzheimer disease(AD) (n = 45) and matched healthy controls (n = 45). The plasma samples of 5 AD patients and 5 matched healthy controls were randomly selected for expression levels of lncRNAs using the TruSeq RNA Sample Prep Kit (Illumina). The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to study the potential of lncRNAs as biomarkers. RESULTS The differential expression profiles of plasma showed that 514 lncRNAs were upregulated, whereas 499 lncRNAs were downregulated.We found that the lncRNAs AL133415.1, AC020916.1, ENST00000654948, ASMTL-AS, AC005730.3, and AP001363.1 levels in the plasma of the AD patients were significantly lower compared to the control group (p1 = 0.0006, p2 < 0.001, p3 < 0.001, p4 = 0.039, p5 = 0.006, p6 < 0.001, respectively). ROC curve analysis revealed that the AUC of AL133415.1 was 0.635 (95% CI]: 0.507-0.763, p = 0.036), the AUC of ASMTL-AS1 was 0.658 (95% CI: 0.513-0.785, p = 0.015), the AUC of AC005730.3 was 0.627 (95%CI: 0.498-0.756, p = 0.049), and the AUC of AP001363.1 was 0.708 (95%CI: 0.595-0.822, p = 0.001). CONCLUSION This study indicated that the plasma levels of the lncRNAs ASMTL-AS1, AP001363.1, AC005730.3, and AL133415.1 might be considered potential biomarkers for AD in the Chinese Population.
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Affiliation(s)
- Yi Cheng
- Department of Public Health, Xinjiang Medical University, Xinjiang, China
- Drug Clinical Institutions, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaohui Zhou
- Department of Geriatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Ting Zou
- Department of Geriatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Lei Zhang
- Department of Geriatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Lihua Li
- Pharmacy, Maternal and Child Health Hospital of Urumqi, Urumqi, China
| | - Chang Yang
- Department of Geriatrics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Long Ma
- Department of Public Health, Xinjiang Medical University, Xinjiang, China
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17
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Zhang C, Zhang Y, Wang Q, Fang Z, Xu X, Zhao M, Xu T. Long non-coding RNAs in intracerebral hemorrhage. Front Mol Neurosci 2023; 16:1119275. [PMID: 37377769 PMCID: PMC10292654 DOI: 10.3389/fnmol.2023.1119275] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 05/18/2023] [Indexed: 06/29/2023] Open
Abstract
Intracerebral hemorrhage (ICH), a subtype of stroke, can lead to long-term disability and is one of the leading causes of death. Unfortunately, the effectiveness of pharmacological therapy for ICH is still uncertain. Long non-coding RNA (lncRNA) was defined as an RNA molecule that consists of more than 200 nt without translational activity. As a vital class of diverse molecules, lncRNAs are involved in developmental and pathological processes and have been attractive for decades. LncRNAs have also become potential targets for therapies, as they were massively identified and profiled. In particular, emerging evidence has revealed the critical role of lncRNAs in ICH while attempts were made to treat ICH via regulating lncRNAs. But the latest evidence remains to be summarized. Thus, in this review, we will summarize the recent advances in lncRNA in ICH, highlighting the regulatory role of lncRNAs and their potential as therapeutic targets.
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Affiliation(s)
- Chenyu Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Ying Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Qi Wang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenwei Fang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Xu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Mengnan Zhao
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Xu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
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18
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Vijay Kumar MJ, Morales R, Tsvetkov AS. G-quadruplexes and associated proteins in aging and Alzheimer's disease. FRONTIERS IN AGING 2023; 4:1164057. [PMID: 37323535 PMCID: PMC10267416 DOI: 10.3389/fragi.2023.1164057] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/17/2023] [Indexed: 06/17/2023]
Abstract
Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer's disease (AD). Alzheimer's disease is characterized by progressive cognitive decline, memory loss, and neuropsychiatric and behavioral symptoms, accounting for most of the reported dementia cases. This disease is now becoming a major challenge and burden on modern society, especially with the aging population. Over the last few decades, a significant understanding of the pathophysiology of AD has been gained by studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, and neuroinflammation. This review focuses on the role of non-canonical secondary structures of DNA/RNA G-quadruplexes (G4s, G4-DNA, and G4-RNA), G4-binding proteins (G4BPs), and helicases, and their roles in aging and AD. Being critically important for cellular function, G4s are involved in the regulation of DNA and RNA processes, such as replication, transcription, translation, RNA localization, and degradation. Recent studies have also highlighted G4-DNA's roles in inducing DNA double-strand breaks that cause genomic instability and G4-RNA's participation in regulating stress granule formation. This review emphasizes the significance of G4s in aging processes and how their homeostatic imbalance may contribute to the pathophysiology of AD.
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Affiliation(s)
- M. J. Vijay Kumar
- The Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, United States
| | - Rodrigo Morales
- The Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, United States
- Centro Integrativo de Biologia y Quimica Aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago, Chile
| | - Andrey S. Tsvetkov
- The Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, United States
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX, United States
- UTHealth Consortium on Aging, The University of Texas McGovern Medical School, Houston, TX, United States
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19
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Ren Z, Chu C, Pang Y, Cai H, Jia L. A Group of Long Non-coding RNAs in Blood Acts as a Specific Biomarker of Alzheimer's Disease. Mol Neurobiol 2023; 60:566-575. [PMID: 36327022 DOI: 10.1007/s12035-022-03105-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
Long non-coding RNAs (lncRNAs) have been identified to be involved in the pathogenesis of Alzheimer's disease (AD). In this study, we evaluated whether lncRNAs can be used to discriminate AD patients from controls and patients with other dementias, such as vascular, Parkinson's disease, behavioral variant frontotemporal, and dementia with Lewy body. In this study, we used three datasets to measure the blood lncRNA levels. A pilot study (dataset 1, n = 40; controls, 20; AD, 20) was used to screen for differentially expressed lncRNAs. Dataset 2 (n = 174; controls, 86; AD, 88) was used to identify a lncRNA panel for the diagnostic model. Dataset 3 (n = 333; control, 60; AD, 54; vascular dementia, 53; Parkinson's disease dementia, 55; behavioral variant frontotemporal dementia, 56; and dementia with Lewy body, 55) was used to validate the diagnostic model. In dataset 1, 12 upregulated and 15 downregulated lncRNAs were identified. In dataset 2, a panel of seven lncRNAs was found to have the ability to differentiate AD patients from controls. Finally, this panel was applied to dataset 3 to successfully distinguish AD from other dementias. This study proposes a panel of seven lncRNAs as specific and promising biomarker for AD diagnosis.
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Affiliation(s)
- Ziye Ren
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, 45 Changchun St., Beijing, China
| | - Changbiao Chu
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, 45 Changchun St., Beijing, China
| | - Yana Pang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, 45 Changchun St., Beijing, China
| | - Huimin Cai
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, 45 Changchun St., Beijing, China
| | - Longfei Jia
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, 45 Changchun St., Beijing, China.
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20
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Xuan C, Yang E, Zhao S, Xu J, Li P, Zhang Y, Jiang Z, Ding X. Regulation of LncRNAs and microRNAs in neuronal development and disease. PeerJ 2023; 11:e15197. [PMID: 37038472 PMCID: PMC10082570 DOI: 10.7717/peerj.15197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 03/15/2023] [Indexed: 04/12/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are RNAs that do not encode proteins but play important roles in regulating cellular processes. Multiple studies over the past decade have demonstrated the role of microRNAs (miRNAs) in cancer, in which some miRNAs can act as biomarkers or provide therapy target. Accumulating evidence also points to the importance of long non-coding RNAs (lncRNAs) in regulating miRNA-mRNA networks. An increasing number of ncRNAs have been shown to be involved in the regulation of cellular processes, and dysregulation of ncRNAs often heralds disease. As the population ages, the incidence of neurodegenerative diseases is increasing, placing enormous pressure on global health systems. Given the excellent performance of ncRNAs in early cancer screening and treatment, here we attempted to aggregate and analyze the regulatory functions of ncRNAs in neuronal development and disease. In this review, we summarize current knowledge on ncRNA taxonomy, biogenesis, and function, and discuss current research progress on ncRNAs in relation to neuronal development, differentiation, and neurodegenerative diseases.
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Affiliation(s)
- Cheng Xuan
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Enyu Yang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Shuo Zhao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Juan Xu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Peihang Li
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Yaping Zhang
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang Province, China
| | - Zhenggang Jiang
- Department of Science Research and Information Management, Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, Zhejiang Province, China
| | - Xianfeng Ding
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
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21
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Jafari-Raddani F, Davoodi-Moghaddam Z, Yousefi AM, Ghaffari SH, Bashash D. An overview of long noncoding RNAs: Biology, functions, therapeutics, analysis methods, and bioinformatics tools. Cell Biochem Funct 2022; 40:800-825. [PMID: 36111699 DOI: 10.1002/cbf.3748] [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: 08/16/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 12/15/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a diverse class of RNAs whose functions are widespread in all branches of life and have been the focus of attention in the last decade. While a huge number of lncRNAs have been identified, there is still much work to be done and plenty to be learned. In the current review, we begin with the biogenesis and function of lncRNAs as they are involved in the different cellular processes from regulating the architecture of chromosomes to controlling translation and post-translation modifications. Questions on how overexpression, mutations, or deficiency of lncRNAs can affect the cellular status and result in the pathogenesis of various human diseases are responded to. Besides, we allocate an overview of several studies, concerning the application of lncRNAs either as diagnostic and prognostic biomarkers or novel therapeutics. We also introduce the currently available techniques to explore details of lncRNAs such as their function, cellular localization, and structure. In the last section, as exponentially growing data in this area need to be gathered and organized in comprehensive databases, we have a particular focus on presenting general and specialized databases. Taken together, with this review, we aim to provide the latest information on different aspects of lncRNAs to highlight their importance in physiopathologic states and take a step towards helping future studies.
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Affiliation(s)
- Farideh Jafari-Raddani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Davoodi-Moghaddam
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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22
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Navigating the Multiverse of Antisense RNAs: The Transcription- and RNA-Dependent Dimension. Noncoding RNA 2022; 8:ncrna8060074. [PMID: 36412909 PMCID: PMC9680235 DOI: 10.3390/ncrna8060074] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 12/14/2022] Open
Abstract
Evidence accumulated over the past decades shows that the number of identified antisense transcripts is continuously increasing, promoting them from transcriptional noise to real genes with specific functions. Indeed, recent studies have begun to unravel the complexity of the antisense RNA (asRNA) world, starting from the multidimensional mechanisms that they can exert in physiological and pathological conditions. In this review, we discuss the multiverse of the molecular functions of asRNAs, describing their action through transcription-dependent and RNA-dependent mechanisms. Then, we report the workflow and methodologies to study and functionally characterize single asRNA candidates.
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23
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Passarella D, Ciampi S, Di Liberto V, Zuccarini M, Ronci M, Medoro A, Foderà E, Frinchi M, Mignogna D, Russo C, Porcile C. Low-Density Lipoprotein Receptor-Related Protein 8 at the Crossroad between Cancer and Neurodegeneration. Int J Mol Sci 2022; 23:ijms23168921. [PMID: 36012187 PMCID: PMC9408729 DOI: 10.3390/ijms23168921] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/07/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
The low-density-lipoprotein receptors represent a family of pleiotropic cell surface receptors involved in lipid homeostasis, cell migration, proliferation and differentiation. The family shares common structural features but also has significant differences mainly due to tissue-specific interactors and to peculiar proteolytic processing. Among the receptors in the family, recent studies place low-density lipoprotein receptor-related protein 8 (LRP8) at the center of both neurodegenerative and cancer-related pathways. From one side, its overexpression has been highlighted in many types of cancer including breast, gastric, prostate, lung and melanoma; from the other side, LRP8 has a potential role in neurodegeneration as apolipoprotein E (ApoE) and reelin receptor, which are, respectively, the major risk factor for developing Alzheimer’s disease (AD) and the main driver of neuronal migration, and as a γ-secretase substrate, the main enzyme responsible for amyloid formation in AD. The present review analyzes the contributions of LDL receptors, specifically of LRP8, in both cancer and neurodegeneration, pointing out that depending on various interactions and peculiar processing, the receptor can contribute to both proliferative and neurodegenerative processes.
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Affiliation(s)
- Daniela Passarella
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Silvia Ciampi
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Valentina Di Liberto
- Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, 90133 Palermo, Italy
| | - Mariachiara Zuccarini
- Department of Medical Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy
| | - Maurizio Ronci
- Department of Pharmacy, University of Chieti-Pescara, 66100 Chieti, Italy
| | - Alessandro Medoro
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Emanuele Foderà
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Monica Frinchi
- Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, 90133 Palermo, Italy
| | - Donatella Mignogna
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
| | - Claudio Russo
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
- Correspondence: ; Tel.: +39-0874404897
| | - Carola Porcile
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
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Villa C, Stoccoro A. Epigenetic Peripheral Biomarkers for Early Diagnosis of Alzheimer's Disease. Genes (Basel) 2022; 13:1308. [PMID: 35893045 PMCID: PMC9332601 DOI: 10.3390/genes13081308] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/20/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and represents the leading cause of cognitive impairment and dementia in older individuals throughout the world. The main hallmarks of AD include brain atrophy, extracellular deposition of insoluble amyloid-β (Aβ) plaques, and the intracellular aggregation of protein tau in neurofibrillary tangles. These pathological modifications start many years prior to clinical manifestations of disease and the spectrum of AD progresses along a continuum from preclinical to clinical phases. Therefore, identifying specific biomarkers for detecting AD at early stages greatly improves clinical management. However, stable and non-invasive biomarkers are not currently available for the early detection of the disease. In the search for more reliable biomarkers, epigenetic mechanisms, able to mediate the interaction between the genome and the environment, are emerging as important players in AD pathogenesis. Herein, we discuss altered epigenetic signatures in blood as potential peripheral biomarkers for the early detection of AD in order to help diagnosis and improve therapy.
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Affiliation(s)
- Chiara Villa
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
| | - Andrea Stoccoro
- Department of Translational Research and of New Surgical and Medical Technologies, Medical School, University of Pisa, 56126 Pisa, Italy;
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25
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Khodayi-Shahrak M, Khalaj-Kondori M, Hosseinpour Feizi MA, Talebi M. Insights into the mechanisms of non-coding RNAs' implication in the pathogenesis of Alzheimer's disease. EXCLI JOURNAL 2022; 21:921-940. [PMID: 36110561 PMCID: PMC9441681 DOI: 10.17179/excli2022-5006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 11/06/2022]
Abstract
Non-coding RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in the regulation of gene expression at transcriptional, posttranscriptional, and epigenetic levels. Several studies in cell lines, animal models, and humans, have revealed that non-coding RNAs play crucial roles in the pathogenesis of Alzheimer's disease (AD). Detailed knowledge on their mechanism of implication in the AD pathogenesis can help to develop novel therapeutic and disease management strategies. The two main pathological hallmarks of AD are amyloid plaques resulting from the β-amyloid accumulation, and neurofibrillary tangles (NFT) due to the phosphorylated tau accumulation. Several lncRNAs and miRNAs play crucial roles in both these hallmarks of the AD pathogenesis and other AD-related pathological procedures such as neuronal and synaptic plasticity, neuroinflammation, neuronal differentiation and neuronal apoptosis. In this review, we outlined the non-coding RNAs and further discussed how they are implicated in these AD-related pathological procedures.
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Affiliation(s)
- Majid Khodayi-Shahrak
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran,*To whom correspondence should be addressed: Mohammad Khalaj-Kondori, Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran, E-mail:
| | | | - Mahnaz Talebi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Varesi A, Carrara A, Pires VG, Floris V, Pierella E, Savioli G, Prasad S, Esposito C, Ricevuti G, Chirumbolo S, Pascale A. Blood-Based Biomarkers for Alzheimer's Disease Diagnosis and Progression: An Overview. Cells 2022; 11:1367. [PMID: 35456047 PMCID: PMC9044750 DOI: 10.3390/cells11081367] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 01/10/2023] Open
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1-42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.
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Affiliation(s)
- Angelica Varesi
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
- Almo Collegio Borromeo, 27100 Pavia, Italy
| | - Adelaide Carrara
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Vitor Gomes Pires
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA;
| | - Valentina Floris
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Elisa Pierella
- School of Medicine, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK;
| | - Gabriele Savioli
- Emergency Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Sakshi Prasad
- Faculty of Medicine, National Pirogov Memorial Medical University, 21018 Vinnytsya, Ukraine;
| | - Ciro Esposito
- Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, 27100 Pavia, Italy;
| | - Giovanni Ricevuti
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy;
| | - Alessia Pascale
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy;
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27
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Ilina A, Khavinson V, Linkova N, Petukhov M. Neuroepigenetic Mechanisms of Action of Ultrashort Peptides in Alzheimer's Disease. Int J Mol Sci 2022; 23:ijms23084259. [PMID: 35457077 PMCID: PMC9032300 DOI: 10.3390/ijms23084259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 12/23/2022] Open
Abstract
Epigenetic regulation of gene expression is necessary for maintaining higher-order cognitive functions (learning and memory). The current understanding of the role of epigenetics in the mechanism of Alzheimer’s disease (AD) is focused on DNA methylation, chromatin remodeling, histone modifications, and regulation of non-coding RNAs. The pathogenetic links of this disease are the misfolding and aggregation of tau protein and amyloid peptides, mitochondrial dysfunction, oxidative stress, impaired energy metabolism, destruction of the blood–brain barrier, and neuroinflammation, all of which lead to impaired synaptic plasticity and memory loss. Ultrashort peptides are promising neuroprotective compounds with a broad spectrum of activity and without reported side effects. The main aim of this review is to analyze the possible epigenetic mechanisms of the neuroprotective action of ultrashort peptides in AD. The review highlights the role of short peptides in the AD pathophysiology. We formulate the hypothesis that peptide regulation of gene expression can be mediated by the interaction of short peptides with histone proteins, cis- and transregulatory DNA elements and effector molecules (DNA/RNA-binding proteins and non-coding RNA). The development of therapeutic agents based on ultrashort peptides may offer a promising addition to the multifunctional treatment of AD.
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Affiliation(s)
- Anastasiia Ilina
- Department of Biogerontology, Saint Petersburg Institute of Bioregulation and Gerontology, 19711 Saint Petersburg, Russia; (V.K.); (N.L.)
- Department of General Pathology and Pathological Physiology, Institute of Experimental Medicine, 197376 Saint Petersburg, Russia
- Correspondence: ; Tel.: +7-(953)145-89-58
| | - Vladimir Khavinson
- Department of Biogerontology, Saint Petersburg Institute of Bioregulation and Gerontology, 19711 Saint Petersburg, Russia; (V.K.); (N.L.)
- Group of Peptide Regulation of Aging, Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 Saint Petersburg, Russia
| | - Natalia Linkova
- Department of Biogerontology, Saint Petersburg Institute of Bioregulation and Gerontology, 19711 Saint Petersburg, Russia; (V.K.); (N.L.)
| | - Mikhael Petukhov
- Department of Molecular Radiation Biophysics, Petersburg Nuclear Physics Institute Named after B.P. Konstantinov, NRC “Kurchatov Institute”, 188300 Gatchina, Russia;
- Group of Biophysics, Higher Engineering and Technical School, Peter the Great St. Petersburg Polytechnic University, 195251 Saint Petersburg, Russia
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28
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Ni YQ, Xu H, Liu YS. Roles of Long Non-coding RNAs in the Development of Aging-Related Neurodegenerative Diseases. Front Mol Neurosci 2022; 15:844193. [PMID: 35359573 PMCID: PMC8964039 DOI: 10.3389/fnmol.2022.844193] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/09/2022] [Indexed: 12/12/2022] Open
Abstract
Aging-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.
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Affiliation(s)
- Yu-Qing Ni
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, China
- Institute of Aging and Age-Related Disease Research, Central South University, Changsha, China
| | - Hui Xu
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, China
- Institute of Aging and Age-Related Disease Research, Central South University, Changsha, China
| | - You-Shuo Liu
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, China
- Institute of Aging and Age-Related Disease Research, Central South University, Changsha, China
- *Correspondence: You-Shuo Liu,
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29
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Lan Z, Chen Y, Jin J, Xu Y, Zhu X. Long Non-coding RNA: Insight Into Mechanisms of Alzheimer's Disease. Front Mol Neurosci 2022; 14:821002. [PMID: 35095418 PMCID: PMC8795976 DOI: 10.3389/fnmol.2021.821002] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD), a heterogeneous neurodegenerative disorder, is the most common cause of dementia accounting for an estimated 60–80% of cases. The pathogenesis of AD remains unclear, and no curative treatment is available so far. Increasing evidence has revealed a vital role of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), in AD. LncRNAs contribute to the pathogenesis of AD via modulating amyloid production, Tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, synaptic impairment and neuroinflammation. This review describes the biological functions and mechanisms of lncRNAs in AD, indicating that lncRNAs may provide potential therapeutic targets for the diagnosis and treatment of AD.
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Affiliation(s)
- Zhen Lan
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
| | - Yanting Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Jiali Jin
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
- Institute of Brain Sciences, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China
| | - Xiaolei Zhu
- Department of Neurology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, the Affiliated Hospital of Nanjing University Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China
- Institute of Brain Sciences, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China
- *Correspondence: Xiaolei Zhu
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Gao X, Chen Q, Yao H, Tan J, Liu Z, Zhou Y, Zou Z. Epigenetics in Alzheimer's Disease. Front Aging Neurosci 2022; 14:911635. [PMID: 35813941 PMCID: PMC9260511 DOI: 10.3389/fnagi.2022.911635] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/24/2022] [Indexed: 12/19/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease with unknown pathogenesis and complex pathological manifestations. At present, a large number of studies on targeted drugs for the typical pathological phenomenon of AD (Aβ) have ended in failure. Although there are some drugs on the market that indirectly act on AD, their efficacy is very low and the side effects are substantial, so there is an urgent need to develop a new strategy for the treatment of AD. An increasing number of studies have confirmed epigenetic changes in AD. Although it is not clear whether these epigenetic changes are the cause or result of AD, they provide a new avenue of treatment for medical researchers worldwide. This article summarizes various epigenetic changes in AD, including DNA methylation, histone modification and miRNA, and concludes that epigenetics has great potential as a new target for the treatment of AD.
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Affiliation(s)
- Xiaodie Gao
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- Department of Scientific Research, Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
| | - Qiang Chen
- Department of Scientific Research, Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
| | - Hua Yao
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
| | - Jie Tan
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
| | - Zheng Liu
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- *Correspondence: Zheng Liu,
| | - Yan Zhou
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- Yan Zhou,
| | - Zhenyou Zou
- Guangxi Key Lab of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, China
- Department of Scientific Research, Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, China
- Zhenyou Zou,
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31
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Policarpo R, d’Ydewalle C. Missing lnc(RNAs) in Alzheimer's Disease? Genes (Basel) 2021; 13:39. [PMID: 35052379 PMCID: PMC8774680 DOI: 10.3390/genes13010039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 12/26/2022] Open
Abstract
With the ongoing demographic shift towards increasingly elderly populations, it is estimated that approximately 150 million people will live with Alzheimer's disease (AD) by 2050. By then, AD will be one of the most burdensome diseases of this and potentially next centuries. Although its exact etiology remains elusive, both environmental and genetic factors play crucial roles in the mechanisms underlying AD neuropathology. Genome-wide association studies (GWAS) identified genetic variants associated with AD susceptibility in more than 40 different genomic loci. Most of these disease-associated variants reside in non-coding regions of the genome. In recent years, it has become clear that functionally active transcripts arise from these non-coding loci. One type of non-coding transcript, referred to as long non-coding RNAs (lncRNAs), gained significant attention due to their multiple roles in neurodevelopment, brain homeostasis, aging, and their dysregulation or dysfunction in neurological diseases including in AD. Here, we will summarize the current knowledge regarding genetic variations, expression profiles, as well as potential functions, diagnostic or therapeutic roles of lncRNAs in AD. We postulate that lncRNAs may represent the missing link in AD pathology and that unraveling their role may open avenues to better AD treatments.
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Affiliation(s)
- Rafaela Policarpo
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium;
- Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, 3000 Leuven, Belgium
- Neuroscience Discovery, Janssen Research & Development, Janssen Pharmaceutica N.V., 2340 Beerse, Belgium
| | - Constantin d’Ydewalle
- Neuroscience Discovery, Janssen Research & Development, Janssen Pharmaceutica N.V., 2340 Beerse, Belgium
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Rabaneda-Bueno R, Mena-Montes B, Torres-Castro S, Torres-Carrillo N, Torres-Carrillo NM. Advances in Genetics and Epigenetic Alterations in Alzheimer's Disease: A Notion for Therapeutic Treatment. Genes (Basel) 2021; 12:1959. [PMID: 34946908 PMCID: PMC8700838 DOI: 10.3390/genes12121959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 12/18/2022] Open
Abstract
Alzheimer's disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.
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Affiliation(s)
- Rubén Rabaneda-Bueno
- Biology Centre of the Czech Academy of Sciences, Institute of Hydrobiology, 37005 České Budějovice, Czech Republic
- School of Biological Sciences, James Clerk Maxwell Building, The King’s Buildings Campus, University of Edinburgh, Edinburgh EH9 3FD, UK
| | - Beatriz Mena-Montes
- Laboratorio de Biología del Envejecimiento, Departamento de Investigación Básica, Instituto Nacional de Geriatría, Mexico City 10200, Mexico;
| | - Sara Torres-Castro
- Departamento de Epidemiología Demográfica y Determinantes Sociales, Instituto Nacional de Geriatría, Mexico City 10200, Mexico;
| | - Norma Torres-Carrillo
- Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (N.T.-C.); (N.M.T.-C.)
| | - Nora Magdalena Torres-Carrillo
- Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (N.T.-C.); (N.M.T.-C.)
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33
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Abramenko IV, Bilous NI, Chumak AA, Diagil IS, Martina ZV. THE EXPRESSION OF THE MAIN AND ALTERNATIVE TRANSCRIPT (SORL1 Delta2) OF THE SORL1 GENE IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS AFFECTED BY THE CHORNOBYL ACCIDENT. PROBLEMY RADIATSIINOI MEDYTSYNY TA RADIOBIOLOHII 2021; 26:273-283. [PMID: 34965554 DOI: 10.33145/2304-8336-2021-26-273-283] [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: 07/26/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE to study clinical-hematological data and expression of the main and alternative transcripts of SORL1 genein chronic lymphocytic leukemia (CLL) patients affected by the Chornobyl catastrophe. METHODS Analysis was performed in the main group of 34 CLL patients irradiated due to the Chornobyl NPP acci-dent (30 clean-up workers, and 4 evacuees) and in the control group of 27 non-irradiated CLL patients. Groups ofpatients were comparable by age, sex, stage of disease, mutational status of IGHV genes. Expression of the main andalternative transcripts of SORL1 gene was evaluated by Quantitative Real-time polymerase chain reaction (PCR). TheIGHV gene mutational status, TP53 and SF3B1 mutations were studied by PCR followed by direct sequencing. Data wereanalyzed with the SPSS software package, version 20.0. RESULTS Relative expression level of the main transcript of SORL1 gene was low (mean 1.71 ± 0.55, median 0.57),did not correlate with the IGHV gene mutational status, TP53 and SF3B1 mutations, stage of disease. The expressionof B transcript was not detected, F transcript was expressed at a very low level in 9 patients. The average relativeexpression level of SORL1-Δ2 transcript was 14.1 ± 6.04 (median 3.48; range 0.01-90.51). The expression of SORL1-Δ2transcript above the median was more frequent among patients on C stage (p = 0.001), and in patients with unmu-tated IGHV genes was associated with an extremely negative course of CLL (median of overall survival 9 months vs61 months at low expression). Relative expression levels of the main and alternative transcripts of SORL1 gene inpatients of the main and the control groups did not differ. CONCLUSIONS Our preliminary data suggest that increased expression of SORL1-Δ2 transcript in CLL patients withunmutated IGHV genes can be considered as a negative prognostic marker.
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MESH Headings
- Adult
- Aged
- Chernobyl Nuclear Accident
- Female
- Gene Expression Regulation, Leukemic
- Humans
- LDL-Receptor Related Proteins/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/physiopathology
- Leukemia, Radiation-Induced/genetics
- Leukemia, Radiation-Induced/physiopathology
- Male
- Membrane Transport Proteins/genetics
- Middle Aged
- Mutation
- Occupational Exposure/adverse effects
- Radiation Exposure/adverse effects
- Radioactive Hazard Release
- Transcription, Genetic
- Ukraine
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Affiliation(s)
- I V Abramenko
- State Institution National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine
| | - N I Bilous
- State Institution National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine
| | - A A Chumak
- State Institution National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine
| | - I S Diagil
- State Institution National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine
| | - Z V Martina
- State Institution National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine, 53 Yuriia Illienka Str., Kyiv, 04050, Ukraine
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34
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Irwin AB, Bahabry R, Lubin FD. A putative role for lncRNAs in epigenetic regulation of memory. Neurochem Int 2021; 150:105184. [PMID: 34530054 PMCID: PMC8552959 DOI: 10.1016/j.neuint.2021.105184] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022]
Abstract
The central dogma of molecular genetics is defined as encoded genetic information within DNA, transcribed into messenger RNA, which contain the instructions for protein synthesis, thus imparting cellular functionality and ultimately life. This molecular genetic theory has given birth to the field of neuroepigenetics, and it is now well established that epigenetic regulation of gene transcription is critical to the learning and memory process. In this review, we address a potential role for a relatively new player in the field of epigenetic crosstalk - long non-coding RNAs (lncRNAs). First, we briefly summarize epigenetic mechanisms in memory formation and examine what little is known about the emerging role of lncRNAs during this process. We then focus discussions on how lncRNAs interact with epigenetic mechanisms to control transcriptional programs under various conditions in the brain, and how this may be applied to regulation of gene expression necessary for memory formation. Next, we explore how epigenetic crosstalk in turn serves to regulate expression of various individual lncRNAs themselves. To highlight the importance of further exploring the role of lncRNA in epigenetic regulation of gene expression, we consider the significant relationship between lncRNA dysregulation and declining memory reserve with aging, Alzheimer's disease, and epilepsy, as well as the promise of novel therapeutic interventions. Finally, we conclude with a discussion of the critical questions that remain to be answered regarding a role for lncRNA in memory.
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Affiliation(s)
- Ashleigh B Irwin
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rudhab Bahabry
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Farah D Lubin
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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35
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Asadi MR, Hassani M, Kiani S, Sabaie H, Moslehian MS, Kazemi M, Ghafouri-Fard S, Taheri M, Rezazadeh M. The Perspective of Dysregulated LncRNAs in Alzheimer's Disease: A Systematic Scoping Review. Front Aging Neurosci 2021; 13:709568. [PMID: 34621163 PMCID: PMC8490871 DOI: 10.3389/fnagi.2021.709568] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/12/2021] [Indexed: 12/22/2022] Open
Abstract
LncRNAs act as part of non-coding RNAs at high levels of complex and stimulatory configurations in basic molecular mechanisms. Their extensive regulatory activity in the CNS continues on a small scale, from the functions of synapses to large-scale neurodevelopment and cognitive functions, aging, and can be seen in both health and disease situations. One of the vast consequences of the pathological role of dysregulated lncRNAs in the CNS due to their role in a network of regulatory pathways can be manifested in Alzheimer's as a neurodegenerative disease. The disease is characterized by two main hallmarks: amyloid plaques due to the accumulation of β-amyloid components and neurofibrillary tangles (NFT) resulting from the accumulation of phosphorylated tau. Numerous studies in humans, animal models, and various cell lines have revealed the role of lncRNAs in the pathogenesis of Alzheimer's disease. This scoping review was performed with a six-step strategy and based on the Prisma guideline by systematically searching the publications of seven databases. Out of 1,591 records, 69 articles were utterly aligned with the specified inclusion criteria and were summarized in the relevant table. Most of the studies were devoted to BACE1-AS, NEAT1, MALAT1, and SNHG1 lncRNAs, respectively, and about one-third of the studies investigated a unique lncRNA. About 56% of the studies reported up-regulation, and 7% reported down-regulation of lncRNAs expressions. Overall, this study was conducted to investigate the association between lncRNAs and Alzheimer's disease to make a reputable source for further studies and find more molecular therapeutic goals for this disease.
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Affiliation(s)
- Mohammad Reza Asadi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Hassani
- Student Research Committee, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Shiva Kiani
- Department of Molecular Genetics, School of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hani Sabaie
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Marziyeh Sadat Moslehian
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Kazemi
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Rezazadeh
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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36
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Zhou S, Yu X, Wang M, Meng Y, Song D, Yang H, Wang D, Bi J, Xu S. Long Non-coding RNAs in Pathogenesis of Neurodegenerative Diseases. Front Cell Dev Biol 2021; 9:719247. [PMID: 34527672 PMCID: PMC8435612 DOI: 10.3389/fcell.2021.719247] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022] Open
Abstract
Emerging evidence addresses the link between the aberrant epigenetic regulation of gene expression and numerous diseases including neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). LncRNAs, a class of ncRNAs, have length of 200 nt or more, some of which crucially regulate a variety of biological processes such as epigenetic-mediated chromatin remodeling, mRNA stability, X-chromosome inactivation and imprinting. Aberrant regulation of the lncRNAs contributes to pathogenesis of many diseases, such as the neurological disorders at the transcriptional and post-transcriptional levels. In this review, we highlight the latest research progress on the contributions of some lncRNAs to the pathogenesis of neurodegenerative diseases via varied mechanisms, such as autophagy regulation, Aβ deposition, neuroinflammation, Tau phosphorylation and α-synuclein aggregation. Meanwhile, we also address the potential challenges on the lncRNAs-mediated epigenetic study to further understand the molecular mechanism of the neurodegenerative diseases.
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Affiliation(s)
- Shiyue Zhou
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiao Yu
- Department of Nutrition, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Min Wang
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yujie Meng
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Dandan Song
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hui Yang
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Dewei Wang
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jianzhong Bi
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shunliang Xu
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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37
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New RNA-Based Breakthroughs in Alzheimer's Disease Diagnosis and Therapeutics. Pharmaceutics 2021; 13:pharmaceutics13091397. [PMID: 34575473 PMCID: PMC8471423 DOI: 10.3390/pharmaceutics13091397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 01/25/2023] Open
Abstract
Dementia is described as the fifth leading cause of death worldwide and Alzheimer’s disease (AD) is recognized as the most common, causing a huge impact on health costs and quality of patients’ lives. The main hallmarks that are commonly associated with the pathologic process are amyloid deposition, pathologic Tau phosphorylation and neurodegeneration. It is still unclear how these events are linked to the disease progression, due to the complex pathologic mechanisms. Nevertheless, several hypotheses have been proposed for a better understanding of AD. The AD diagnosis is performed by using a combination of several tools to detect β-amyloid peptide (Aβ) deposits and modifications in cognitive performance, sometimes being expensive and invasive. In the treatment field, there is still an absence of effective treatments to delay or stop the progression of the disease, with most of the approved drugs used to relieve symptoms, and all of them with significant adverse side effects. Considering all limitations, the need to establish new and more effective diagnostic and therapeutic strategies becomes clear. This review aims not only to describe the disease and its impact but also to collect the currently available diagnostic and therapeutic strategies, highlighting new promising RNA-based strategies for AD.
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38
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Bhattacharyya N, Pandey V, Bhattacharyya M, Dey A. Regulatory role of long non coding RNAs (lncRNAs) in neurological disorders: From novel biomarkers to promising therapeutic strategies. Asian J Pharm Sci 2021; 16:533-550. [PMID: 34849161 PMCID: PMC8609388 DOI: 10.1016/j.ajps.2021.02.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/28/2021] [Accepted: 02/18/2021] [Indexed: 01/12/2023] Open
Abstract
Long non coding RNAs (lncRNAs) are non-protein or low-protein coding transcripts that contain more than 200 nucleotides. They representing a large share of the cell's transcriptional output, demonstrate functional attributes viz. tissue-specific expression, determination of cell fate, controlled expression, RNA processing and editing, dosage compensation, genomic imprinting, conserved evolutionary traits etc. These long non coding variants are well associated with pathogenicity of various diseases including the neurological disorders like Alzheimer's disease, schizophrenia, Huntington's disease, Parkinson's disease etc. Neurological disorders are widespread and there knowing the underlying mechanisms become crucial. The lncRNAs take part in the pathogenesis by a plethora of mechanisms like decoy, scaffold, mi-RNA sequestrator, histone modifiers and in transcriptional interference. Detailed knowledge of the role of lncRNAs can help to use them further as novel biomarkers for therapeutic aspects. Here, in this review we discuss regulation and functional roles of lncRNAs in eight neurological diseases and psychiatric disorders, and the mechanisms by which they act. With these, we try to establish their roles as potential markers and viable diagnostic tools in these disorders.
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Affiliation(s)
| | - Vedansh Pandey
- Department of Life Sciences, Presidency University, Kolkata, India
| | | | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, India
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39
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Rybak-Wolf A, Plass M. RNA Dynamics in Alzheimer's Disease. Molecules 2021; 26:5113. [PMID: 34500547 PMCID: PMC8433936 DOI: 10.3390/molecules26175113] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/09/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.
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Affiliation(s)
- Agnieszka Rybak-Wolf
- Max Delbrück Center for Molecular Medicine (MDC), Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
| | - Mireya Plass
- Gene Regulation of Cell Identity, Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908 Barcelona, Spain
- Program for Advancing Clinical Translation of Regenerative Medicine of Catalonia, P-CMR[C], L'Hospitalet del Llobregat, 08908 Barcelona, Spain
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
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40
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Mosquera-Heredia MI, Morales LC, Vidal OM, Barceló E, Silvera-Redondo C, Vélez JI, Garavito-Galofre P. Exosomes: Potential Disease Biomarkers and New Therapeutic Targets. Biomedicines 2021; 9:1061. [PMID: 34440265 PMCID: PMC8393483 DOI: 10.3390/biomedicines9081061] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023] Open
Abstract
Exosomes are extracellular vesicles released by cells, both constitutively and after cell activation, and are present in different types of biological fluid. Exosomes are involved in the pathogenesis of diseases, such as cancer, neurodegenerative diseases, pregnancy disorders and cardiovascular diseases, and have emerged as potential non-invasive biomarkers for the detection, prognosis and therapeutics of a myriad of diseases. In this review, we describe recent advances related to the regulatory mechanisms of exosome biogenesis, release and molecular composition, as well as their role in health and disease, and their potential use as disease biomarkers and therapeutic targets. In addition, the advantages and disadvantages of their main isolation methods, characterization and cargo analysis, as well as the experimental methods used for exosome-mediated drug delivery, are discussed. Finally, we present potential perspectives for the use of exosomes in future clinical practice.
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Affiliation(s)
- Maria I. Mosquera-Heredia
- Department of Medicine, Universidad del Norte, Barranquilla 081007, Colombia; (L.C.M.); (O.M.V.); (C.S.-R.)
| | - Luis C. Morales
- Department of Medicine, Universidad del Norte, Barranquilla 081007, Colombia; (L.C.M.); (O.M.V.); (C.S.-R.)
| | - Oscar M. Vidal
- Department of Medicine, Universidad del Norte, Barranquilla 081007, Colombia; (L.C.M.); (O.M.V.); (C.S.-R.)
| | - Ernesto Barceló
- Instituto Colombiano de Neuropedagogía, Barranquilla 080020, Colombia;
| | - Carlos Silvera-Redondo
- Department of Medicine, Universidad del Norte, Barranquilla 081007, Colombia; (L.C.M.); (O.M.V.); (C.S.-R.)
| | - Jorge I. Vélez
- Department of Industrial Engineering, Universidad del Norte, Barranquilla 081007, Colombia;
| | - Pilar Garavito-Galofre
- Department of Medicine, Universidad del Norte, Barranquilla 081007, Colombia; (L.C.M.); (O.M.V.); (C.S.-R.)
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41
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Policarpo R, Sierksma A, De Strooper B, d'Ydewalle C. From Junk to Function: LncRNAs in CNS Health and Disease. Front Mol Neurosci 2021; 14:714768. [PMID: 34349622 PMCID: PMC8327212 DOI: 10.3389/fnmol.2021.714768] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 06/25/2021] [Indexed: 12/26/2022] Open
Abstract
Recent advances in RNA sequencing technologies helped to uncover the existence of tens of thousands of long non-coding RNAs (lncRNAs) that arise from the dark matter of the genome. These lncRNAs were originally thought to be transcriptional noise but an increasing number of studies demonstrate that these transcripts can modulate protein-coding gene expression by a wide variety of transcriptional and post-transcriptional mechanisms. The spatiotemporal regulation of lncRNA expression is particularly evident in the central nervous system, suggesting that they may directly contribute to specific brain processes, including neurogenesis and cellular homeostasis. Not surprisingly, lncRNAs are therefore gaining attention as putative novel therapeutic targets for disorders of the brain. In this review, we summarize the recent insights into the functions of lncRNAs in the brain, their role in neuronal maintenance, and their potential contribution to disease. We conclude this review by postulating how these RNA molecules can be targeted for the treatment of yet incurable neurological disorders.
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Affiliation(s)
- Rafaela Policarpo
- VIB-KU Leuven Center For Brain & Disease Research, Leuven, Belgium.,Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.,Neuroscience Discovery, Janssen Research & Development, Janssen Pharmaceutica N.V., Beerse, Belgium
| | - Annerieke Sierksma
- VIB-KU Leuven Center For Brain & Disease Research, Leuven, Belgium.,Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
| | - Bart De Strooper
- VIB-KU Leuven Center For Brain & Disease Research, Leuven, Belgium.,Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.,UK Dementia Research Institute, University College London, London, United Kingdom
| | - Constantin d'Ydewalle
- Neuroscience Discovery, Janssen Research & Development, Janssen Pharmaceutica N.V., Beerse, Belgium
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42
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Zhang Y, Zhao Y, Ao X, Yu W, Zhang L, Wang Y, Chang W. The Role of Non-coding RNAs in Alzheimer's Disease: From Regulated Mechanism to Therapeutic Targets and Diagnostic Biomarkers. Front Aging Neurosci 2021; 13:654978. [PMID: 34276336 PMCID: PMC8283767 DOI: 10.3389/fnagi.2021.654978] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/11/2021] [Indexed: 01/05/2023] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. AD is characterized by the production and aggregation of beta-amyloid (Aβ) peptides, hyperphosphorylated tau proteins that form neurofibrillary tangles (NFTs), and subsequent neuroinflammation, synaptic dysfunction, autophagy and oxidative stress. Non-coding RNAs (ncRNAs) can be used as potential therapeutic targets and biomarkers due to their vital regulatory roles in multiple biological processes involved in disease development. The involvement of ncRNAs in the pathogenesis of AD has been increasingly recognized. Here, we review the ncRNAs implicated in AD and elaborate on their main regulatory pathways, which might have contributions for discovering novel therapeutic targets and drugs for AD.
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Affiliation(s)
- Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yanfang Zhao
- Institute of Biomedical Research, School for Life Science, Shandong University of Technology, Zibo, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao University, Qingdao, China
| | - Lei Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yu Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Wenguang Chang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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43
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Li D, Zhang J, Li X, Chen Y, Yu F, Liu Q. Insights into lncRNAs in Alzheimer's disease mechanisms. RNA Biol 2021; 18:1037-1047. [PMID: 32605500 PMCID: PMC8216181 DOI: 10.1080/15476286.2020.1788848] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common dementia among the elderly. The pathophysiology of AD is characterized by two hallmarks: amyloid plaques, produced by amyloid β (Aβ) aggregation, and neurofibrillary tangle (NFT), produced by accumulation of phosphorylated tau. The regulatory roles of non-coding RNAs (ncRNAs), particularly long noncoding RNAs (lncRNAs), have been widely recognized in gene expression at the transcriptional and posttranscriptional levels. Mounting evidence shows that lncRNAs are aberrantly expressed in AD progression. Here, we review the lncRNAs that implicated in the regulation of Aβ peptide, tau, inflammation, cell death, and other aspects which are the main mechanisms of AD pathology. We also discuss the possible clinical or therapeutic utility of lncRNA detection or targeting to help diagnose or possibly combat AD.
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Affiliation(s)
- Dingfeng Li
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Juan Zhang
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Xiaohui Li
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
| | - Yuhua Chen
- Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Feng Yu
- Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Qiang Liu
- Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
- Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, China
- CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
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44
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Keihani S, Kluever V, Fornasiero EF. Brain Long Noncoding RNAs: Multitask Regulators of Neuronal Differentiation and Function. Molecules 2021; 26:molecules26133951. [PMID: 34203457 PMCID: PMC8272081 DOI: 10.3390/molecules26133951] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/21/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
The extraordinary cellular diversity and the complex connections established within different cells types render the nervous system of vertebrates one of the most sophisticated tissues found in living organisms. Such complexity is ensured by numerous regulatory mechanisms that provide tight spatiotemporal control, robustness and reliability. While the unusual abundance of long noncoding RNAs (lncRNAs) in nervous tissues was traditionally puzzling, it is becoming clear that these molecules have genuine regulatory functions in the brain and they are essential for neuronal physiology. The canonical view of RNA as predominantly a 'coding molecule' has been largely surpassed, together with the conception that lncRNAs only represent 'waste material' produced by cells as a side effect of pervasive transcription. Here we review a growing body of evidence showing that lncRNAs play key roles in several regulatory mechanisms of neurons and other brain cells. In particular, neuronal lncRNAs are crucial for orchestrating neurogenesis, for tuning neuronal differentiation and for the exact calibration of neuronal excitability. Moreover, their diversity and the association to neurodegenerative diseases render them particularly interesting as putative biomarkers for brain disease. Overall, we foresee that in the future a more systematic scrutiny of lncRNA functions will be instrumental for an exhaustive understanding of neuronal pathophysiology.
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45
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Sharma VK, Mehta V, Singh TG. Alzheimer's Disorder: Epigenetic Connection and Associated Risk Factors. Curr Neuropharmacol 2021; 18:740-753. [PMID: 31989902 PMCID: PMC7536832 DOI: 10.2174/1570159x18666200128125641] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 11/26/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
The gene based therapeutics and drug targets have shown incredible and appreciable advances in alleviating human sufferings and complexities. Epigenetics simply means above genetics or which controls the organism beyond genetics. At present it is very clear that all characteristics of an individual are not determined by DNA alone, rather the environment, stress, life style and nutrition play a vital part in determining the response of an organism. Thus, nature (genetic makeup) and nurture (exposure) play equally important roles in the responses observed, both at the cellular and organism levels. Epigenetics influence plethora of complications at cellular and molecular levels that includes cancer, metabolic and cardiovascular complications including neurological (psychosis) and neurodegenerative disorders (Alzheimer’s disease, Parkinson disease etc.). The epigenetic mechanisms include DNA methylation, histone modification and non coding RNA which have substantial impact on progression and pathways linked to Alzheimer’s disease. The epigenetic mechanism gets deregulated in Alzheimer’s disease and is characterized by DNA hyper methylation, deacetylation of histones and general repressed chromatin state which alter gene expression at the transcription level by upregulation, downregulation or silencing of genes. Thus, the processes or modulators of these epigenetic processes have shown vast potential as a therapeutic target in Alzheimer’s disease.
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Affiliation(s)
| | - Vineet Mehta
- Govt. College of Pharmacy, Rohru, District Shimla, Himachal Pradesh-171207, India
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Aliperti V, Skonieczna J, Cerase A. Long Non-Coding RNA (lncRNA) Roles in Cell Biology, Neurodevelopment and Neurological Disorders. Noncoding RNA 2021; 7:36. [PMID: 34204536 PMCID: PMC8293397 DOI: 10.3390/ncrna7020036] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 02/08/2023] Open
Abstract
Development is a complex process regulated both by genetic and epigenetic and environmental clues. Recently, long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression in several tissues including the brain. Altered expression of lncRNAs has been linked to several neurodegenerative, neurodevelopmental and mental disorders. The identification and characterization of lncRNAs that are deregulated or mutated in neurodevelopmental and mental health diseases are fundamental to understanding the complex transcriptional processes in brain function. Crucially, lncRNAs can be exploited as a novel target for treating neurological disorders. In our review, we first summarize the recent advances in our understanding of lncRNA functions in the context of cell biology and then discussing their association with selected neuronal development and neurological disorders.
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Affiliation(s)
- Vincenza Aliperti
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy
| | - Justyna Skonieczna
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK;
| | - Andrea Cerase
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK;
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Poddar MK, Banerjee S, Chakraborty A, Dutta D. Metabolic disorder in Alzheimer's disease. Metab Brain Dis 2021; 36:781-813. [PMID: 33638805 DOI: 10.1007/s11011-021-00673-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 01/14/2021] [Indexed: 12/21/2022]
Abstract
Alzheimer's disease (AD), a well known aging-induced neurodegenerative disease is related to amyloid proteinopathy. This proteinopathy occurs due to abnormalities in protein folding, structure and thereby its function in cells. The root cause of such kind of proteinopathy and its related neurodegeneration is a disorder in metabolism, rather metabolomics of the major as well as minor nutrients. Metabolomics is the most relevant "omics" platform that offers a great potential for the diagnosis and prognosis of neurodegenerative diseases as an individual's metabolome. In recent years, the research on such kinds of neurodegenerative diseases, especially aging-related disorders is broadened its scope towards metabolic function. Different neurotransmitter metabolisms are also involved with AD and its associated neurodegeneration. The genetic and epigenetic backgrounds are also noteworthy. In this review, the physiological changes of AD in relation to its corresponding biochemical, genetic and epigenetic involvements including its (AD) therapeutic aspects are discussed.
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Affiliation(s)
- Mrinal K Poddar
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India.
| | - Soumyabrata Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India
- Departrment of Psychology, Neuroscience Program, Field Neurosciences Institute Research Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, 48859, USA
| | - Apala Chakraborty
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India
| | - Debasmita Dutta
- Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, 700032, India
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, 58102, USA
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Tang L, Xiang Q, Xiang J, Li J. lncRNA-Associated Competitive Endogenous RNA Regulatory Network in an Aβ 25-35-Induced AD Mouse Model Treated with Tripterygium Glycoside. Neuropsychiatr Dis Treat 2021; 17:1531-1541. [PMID: 34040378 PMCID: PMC8141406 DOI: 10.2147/ndt.s310271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/04/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Tripterygium glycoside (TG) has been suggested to have protective effects on the diseases of the central nervous system including Alzheimer's disease (AD). The mechanisms involving lncRNA-associated competing endogenous RNAs (ceRNAs) were shown to play important roles in the development of AD. However, the ceRNA mechanism of TG in treating AD is still unknown. Thus, we aimed to explore the ceRNA mechanism in the treatment of AD with TG. METHODS A total of 32 C57BL/6J mice were administered 3 µL of Aβ25-35 (dual side, 1 mg/mL) by a single stereotactic injection in the brain to conduct AD mouse model. AD mouse models were randomly selected and divided into the AD+normal saline (NS) group (n=16) and the AD+TG group (n=16). The expression data of lncRNAs, mRNAs, and miRNAs in the hippocampus of mice from AD+NS group (n=3) and the AD+TG group (n=3) were obtained by microarray analysis. The MuTaME method was used to predict the ceRNA regulatory network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID database. A protein-protein interaction (PPI) network was constructed by using STRING software. RESULTS TG can significantly improve spatial memory and inhibit the production of p-tau in an Aβ25-35-induced AD mouse model. A total of 661 differentially expressed lncRNAs, 503 mRNAs, and 13 miRNAs were identified. A ceRNA network involving the top 200 mRNA-miRNA-lncRNA pairs with 16 lncRNAs, 11 miRNAs, and 52 mRNAs was visualized. And a PPI network complex filtered 26 gene nodes in DEGs was predicted. CONCLUSION We have identified 503 DEGs, 661 DElncRNAs, and 13 DEmiRNAs during treatment with TG in Aβ25-35-induced AD mouse model. A ceRNA network based on the DElncRNAs, DEmRNAs, and DEmiRNAs was conducted, which provided new insight into the lncRNA-mediated ceRNA regulatory mechanisms underlying the effects of TG in the treatment of AD.
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Affiliation(s)
- Liang Tang
- Department of Basic Biology, Changsha Medical College, Changsha, People’s Republic of China
- Department of Basic Biology, Wuzhou Medical College, Wuzhou, People’s Republic of China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, People’s Republic of China
- Academics Working Station, Changsha Medical College, Changsha, People’s Republic of China
| | - Qin Xiang
- Department of Basic Biology, Changsha Medical College, Changsha, People’s Republic of China
- Department of Basic Biology, Wuzhou Medical College, Wuzhou, People’s Republic of China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, People’s Republic of China
- Academics Working Station, Changsha Medical College, Changsha, People’s Republic of China
| | - Ju Xiang
- Department of Basic Biology, Changsha Medical College, Changsha, People’s Republic of China
- Department of Basic Biology, Wuzhou Medical College, Wuzhou, People’s Republic of China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, People’s Republic of China
- Academics Working Station, Changsha Medical College, Changsha, People’s Republic of China
| | - Jianming Li
- Department of Basic Biology, Changsha Medical College, Changsha, People’s Republic of China
- Department of Basic Biology, Wuzhou Medical College, Wuzhou, People’s Republic of China
- Center for Neuroscience and Behavior, Changsha Medical College, Changsha, People’s Republic of China
- Academics Working Station, Changsha Medical College, Changsha, People’s Republic of China
- Department of Rehabilitation, Xiangya Boai Rehabilitation Hospital, Changsha, 410100, People’s Republic of China
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Yang S, Lim KH, Kim SH, Joo JY. Molecular landscape of long noncoding RNAs in brain disorders. Mol Psychiatry 2021; 26:1060-1074. [PMID: 33173194 DOI: 10.1038/s41380-020-00947-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/28/2020] [Accepted: 10/27/2020] [Indexed: 02/08/2023]
Abstract
According to current paradigms, various risk factors, such as genetic mutations, oxidative stress, neural network dysfunction, and abnormal protein degradation, contribute to the progression of brain disorders. Through the cooperation of gene transcripts in biological processes, the study of noncoding RNAs can lead to insights into the cause and treatment of brain disorders. Recently, long noncoding RNAs (lncRNAs) which are longer than 200 nucleotides in length have been suggested as key factors in various brain disorders. Accumulating evidence suggests the potential of lncRNAs as diagnostic or prognostic biomarkers and therapeutic targets. High-throughput screening-based sequencing has been instrumental in identification of lncRNAs that demand new approaches to understanding the progression of brain disorders. In this review, we discuss the recent progress in the study of lncRNAs, and addresses the pathogenesis of brain disorders that involve lncRNAs and describes the associations of lncRNAs with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and neurodevelopmental disorders. We also discuss potential targets of lncRNAs and their promise as novel therapeutics and biomarkers in brain disorders.
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Affiliation(s)
- Sumin Yang
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Key-Hwan Lim
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Sung-Hyun Kim
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea
| | - Jae-Yeol Joo
- Neurodegenerative Disease Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea.
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Pisignano G, Ladomery M. Epigenetic Regulation of Alternative Splicing: How LncRNAs Tailor the Message. Noncoding RNA 2021; 7:ncrna7010021. [PMID: 33799493 PMCID: PMC8005942 DOI: 10.3390/ncrna7010021] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 12/23/2022] Open
Abstract
Alternative splicing is a highly fine-tuned regulated process and one of the main drivers of proteomic diversity across eukaryotes. The vast majority of human multi-exon genes is alternatively spliced in a cell type- and tissue-specific manner, and defects in alternative splicing can dramatically alter RNA and protein functions and lead to disease. The eukaryotic genome is also intensively transcribed into long and short non-coding RNAs which account for up to 90% of the entire transcriptome. Over the years, lncRNAs have received considerable attention as important players in the regulation of cellular processes including alternative splicing. In this review, we focus on recent discoveries that show how lncRNAs contribute significantly to the regulation of alternative splicing and explore how they are able to shape the expression of a diverse set of splice isoforms through several mechanisms. With the increasing number of lncRNAs being discovered and characterized, the contribution of lncRNAs to the regulation of alternative splicing is likely to grow significantly.
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Affiliation(s)
- Giuseppina Pisignano
- Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
- Correspondence: (G.P.); (M.L.)
| | - Michael Ladomery
- Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Frenchay, Bristol BS16 1QY, UK
- Correspondence: (G.P.); (M.L.)
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