• ACM
• MS
• astrocytes
• brevican
• myelination
• reactive astrocytes

• Animals
• Astrocytes/metabolism
• Myelin Sheath/metabolism
• Humans
• Cells, Cultured
• Central Nervous System/metabolism
• Mice, Inbred C57BL
• Coculture Techniques
• Mice
• Rats
• Encephalomyelitis, Autoimmune, Experimental/metabolism
• Encephalomyelitis, Autoimmune, Experimental/pathology
• Brevican/metabolism
• Female
• Remyelination/physiology
• Oligodendroglia/metabolism

• 362321501/RTG 2413 Deutsche Forschungsgemeinschaft
• 425899996/CRC1436 Deutsche Forschungsgemeinschaft

• HTATIP2/TIP30
• RNA-seq
• T cells
• gene expression
• genome-wide association study (GWAS)
• pediatrics
• type 1 diabetes

• disease-modifying drugs
• history of treatment
• multiple sclerosis
• prospects of treatment
• treatment

• Animals
• Central Nervous System/pathology
• Encephalomyelitis, Autoimmune, Experimental/drug therapy
• Interferon-beta
• Multiple Sclerosis/drug therapy

• Epidermal growth factor
• Experimental CNS demyelinating diseases
• Multiple sclerosis
• Myelin
• Neural stem cells
• Oligodendrocytes

• Animals
• Encephalomyelitis, Autoimmune, Experimental/metabolism
• Epidermal Growth Factor/metabolism
• Epidermal Growth Factor/pharmacology
• Humans
• Mice
• Multiple Sclerosis/metabolism
• Myelin Sheath/metabolism
• Neural Stem Cells/metabolism
• Oligodendroglia/metabolism

• Università degli Studi di Milano

Recent findings showing that epidermal growth factor (EGF) is significantly decreased in the cerebrospinal fluid (CSF) and spinal cord (SC) of living or deceased multiple sclerosis (MS) patients, and that its repeated administration to rodents with chemically- or virally-induced demyelination of the central nervous system (CNS) or experimental allergic encephalomyelitis (EAE) prevents demyelination and inflammatory reactions in the CNS, have led to a critical reassessment of the MS pathogenesis, partly because EGF is considered to have little or no role in immunology. EGF is the only myelinotrophic factor that has been tested in the CSF and spinal cord of MS patients, and it has been shown there is a good correspondence between liquid and tissue levels. This review: (a) briefly summarises the positive EGF effects on neural stem cells, oligodendrocyte cell lineage, and astrocytes in order to explain, at least in part, the biological basis of the myelin loss and remyelination failure in MS; and (b) after a short analysis of the evolution of the principle of cause-effect in the history of Western philosophy, highlights the lack of any experimental immune-, toxin-, or virus-mediated model that precisely reproduces the histopathological features and “clinical” symptoms of MS, thus underlining the inapplicability of Claude Bernard's crucial sequence of “observation, hypothesis, and hypothesis testing.” This is followed by a discussion of most of the putative non-immunologically-linked points of MS pathogenesis (abnormalities in myelinotrophic factor CSF levels, oligodendrocytes (ODCs), astrocytes, extracellular matrix, and epigenetics) on the basis of Popper's falsification principle, and the suggestion that autoimmunity and phologosis reactions (surely the most devasting consequences of the disease) are probably the last links in a chain of events that trigger the reactions. As it is likely that there is a lack of other myelinotrophic growth factors because myelinogenesis is controlled by various CNS and extra-CNS growth factors and other molecules within and outside ODCs, further studies are needed to investigate the role of non-immunological molecules at the time of the onset of the disease. In the words of Galilei, the human mind should be prepared to understand what nature has created.

• epidermal growth factor (EGF)
• epistemology
• experimental CNS demyelinating diseases
• multiple sclerosis pathogenesis
• remyelination failure

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPK^ERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPK^ERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPK^ERK negative feedback phosphatases that normally regulate MAPK^ERK activity. Consequently, these factors may contribute to inappropriate MAPK^ERK overactivity, and thereby to neurodegeneration. Also, MAPK^ERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPK^ERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.

• DUSP6
• Demyelination
• LMP-1
• MAPKERK; Multiple sclerosis
• Microglia

• IkBa
• IκB
• Mallory-Denk-bodies
• NF-kB
• NF-κB
• NMPP
• PPIX
• X-linked protoporphyria
• ZnPP
• ZnPPIX
• affinity proteomics
• erythropoietic protoporphyria
• hepatotoxicity
• immunoaffinity
• inflammation
• inflammatory response
• knockouts*
• label-free quantification
• liver disease
• liver inflammation
• mass spectrometry
• p62
• protein aggregation
• protein-protein interactions
• proteomics.
• α
• β

• Active Transport, Cell Nucleus/drug effects
• Animals
• Autophagy/drug effects
• Cell Nucleus/drug effects
• Cell Nucleus/metabolism
• HEK293 Cells
• HeLa Cells
• Hep G2 Cells
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• I-kappa B Proteins/metabolism
• Inflammation/pathology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B/metabolism
• Nuclear Pore Complex Proteins/metabolism
• Protein Aggregates/drug effects
• Protein Binding/drug effects
• Protein Multimerization/drug effects
• Protoporphyrins/pharmacology
• RNA, Small Interfering/metabolism
• Sequestosome-1 Protein/metabolism
• Solubility

• R35 GM130353 NIGMS NIH HHS
• 81189 CIHR
• R01 GM044037 NIGMS NIH HHS
• R56 DK087984 NIDDK NIH HHS
• R37 GM025515 NIGMS NIH HHS
• R01 DK087984 NIDDK NIH HHS
• R01 GM025515 NIGMS NIH HHS
• R56 DK026506 NIDDK NIH HHS
• R01 GM097057 NIGMS NIH HHS
• R01 DK026506 NIDDK NIH HHS
• P30 DK026743 NIDDK NIH HHS
• HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• HHS | NIH | National Institute of General Medical Sciences (NIGMS)
• Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)
• Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)

To determine whether there are nuclear depletion and cellular mislocalization of RNA-binding proteins (RBPs) transactivation response DNA-binding protein of 43 kDa (TDP-43), fused in sarcoma (FUS), and polypyrimidine tract–binding protein (PTB) in MS, as is the case in amyotrophic lateral sclerosis (ALS) and oligodendrocytes infected with Theiler murine encephalomyelitis virus (TMEV), we examined MS lesions and in vitro cultured primary human brain–derived oligodendrocytes.

Nuclear depletion and mislocalization of TDP-43, FUS, and PTB are thought to contribute to the pathogenesis of ALS and TMEV demyelination. The latter findings prompted us to investigate these RBPs in the demyelinated lesions of MS and in in vitro cultured human brain–derived oligodendrocytes under metabolic stress conditions.

We found (1) mislocalized TDP-43 in oligodendrocytes in active lesions in some patients with MS; (2) decreased PTB1 expression in oligodendrocytes in mixed active/inactive demyelinating lesions; (3) decreased nuclear expression of PTB2 in neurons in cortical demyelinating lesions; and (4) nuclear depletion of TDP-43 in oligodendrocytes under metabolic stress induced by low glucose/low nutrient conditions compared with optimal culture conditions.

TDP-43 has been found to have a key role in oligodendrocyte function and viability, whereas PTB is important in neuronal differentiation, suggesting that altered expression and mislocalization of these RBPs in MS lesions may contribute to the pathogenesis of demyelination and neurodegeneration. Our findings also identify nucleocytoplasmic transport as a target for treatment.

Pathological cardiac overload induces myocardial protein synthesis and hypertrophy, which predisposes to heart failure. To inhibit hypertrophy therapeutically, the identification of negative regulators of cardiomyocyte protein synthesis is needed. Here, we identified the tumor suppressor protein TIP30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP30 levels in mice entailed exaggerated cardiac growth during experimental pressure overload, which was associated with cardiomyocyte cellular hypertrophy, increased myocardial protein synthesis, reduced capillary density, and left ventricular dysfunction. Pharmacological inhibition of protein synthesis improved these defects. Our results are relevant for human disease, since we found diminished cardiac TIP30 levels in samples from patients suffering from end‐stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP30 in mouse hearts inhibited cardiac hypertrophy and improved left ventricular function during pressure overload and in cardiomyopathic mdx mice. Mechanistically, we identified a previously unknown anti‐hypertrophic mechanism, whereby TIP30 binds the eukaryotic elongation factor 1A (eEF1A) to prevent the interaction with its essential co‐factor eEF1B2 and translational elongation. Therefore, TIP30 could be a therapeutic target to counteract cardiac hypertrophy.

• cardiac hypertrophy
• cardiomyopathy
• heart failure
• protein synthesis
• translational elongation

• Local translation
• Myelin
• Neurodegenerative disease
• OPC
• Oligodendrocyte
• Stress

• Animals
• Autopsy
• Cell Line
• Cell Nucleus
• Cells, Cultured
• Cytoplasm
• DNA-Binding Proteins/metabolism
• DNA-Binding Proteins/physiology
• Humans
• Mice
• Protein Transport/physiology
• TDP-43 Proteinopathies/metabolism
• TDP-43 Proteinopathies/physiopathology
• Theilovirus/metabolism
• Theilovirus/pathogenicity

• R21 NS096569 NINDS NIH HHS

Contactin-1 and contactin-2 are important for the maintenance of axonal integrity.

To investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple sclerosis patients and controls, and their potential use as prognostic markers for neurodegeneration.

Cerebrospinal fluid contactin-1 and contactin-2 were measured in relapsing–remitting multiple sclerosis (n = 41), secondary progressive multiple sclerosis (n = 26) and primary progressive multiple sclerosis patients (n = 13) and controls (n = 18), and in a second cohort with clinically isolated syndrome patients (n = 88, median clinical follow-up period of 2.3 years) and controls (n = 20). Correlations/linear regressions were analysed with other baseline cerebrospinal fluid axonal damage markers and cross-sectional/longitudinal magnetic resonance imaging features.

Contactin-1 and contactin-2 levels were up to 1.4-fold reduced in relapsing–remitting multiple sclerosis (contactin-1: p = 0.01, contactin-2: p = 0.02) and secondary progressive multiple sclerosis (contactin-1: p = 0.05, contactin-2: p = 0.02) compared to controls. In clinically isolated syndrome patients, contactin-1 tended to increase when compared to controls (p = 0.07). Both contactin-1 and contactin-2 correlated with neurofilament light, neurofilament heavy and magnetic resonance imaging metrics differently depending on the disease stage. In clinically isolated syndrome patients, baseline contactin-2 level (β = –0.42, p = 0.04) predicted the longitudinal decline in cortex volume.

Cerebrospinal fluid contactin-1 and contactin-2 reveal axonal dysfunction in various stages of multiple sclerosis and their inclusion to the biomarker panel may provide better insight into the extent of axonal damage/dysfunction.

• CSF biomarker
• Contactin
• axonal damage
• multiple sclerosis
• neurofilament

The transport of mitochondria and other cellular components along the axonal microtubule cytoskeleton plays an essential role in neuronal survival. Defects in this system have been linked to a large number of neurological disorders. In multiple sclerosis (MS) and associated models such as experimental autoimmune encephalomyelitis (EAE), alterations in axonal transport have been shown to exist before neurodegeneration occurs. Genome-wide association (GWA) studies have linked several motor proteins to MS susceptibility, while neuropathological studies have shown accumulations of proteins and organelles suggestive for transport deficits. A reduced effectiveness of axonal transport can lead to neurodegeneration through inhibition of mitochondrial motility, disruption of axoglial interaction or prevention of remyelination. In MS, demyelination leads to dysregulation of axonal transport, aggravated by the effects of TNF-alpha, nitric oxide and glutamate on the cytoskeleton. The combined effect of all these pathways is a vicious cycle in which a defective axonal transport system leads to an increase in ATP consumption through loss of membrane organization and a reduction in available ATP through inhibition of mitochondrial transport, resulting in even further inhibition of transport. The persistent activity of this positive feedback loop contributes to neurodegeneration in MS.

• Axonal transport
• Dynein
• Intracellular transport
• Kinesin
• Microtubule
• Mitochondrial transport
• Neurodegeneration

• Adaptor Proteins, Signal Transducing
• Animals
• Astrocytes
• Cell Differentiation/immunology
• Cell Proliferation/physiology
• Coculture Techniques
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Female
• HEK293 Cells
• HeLa Cells
• Humans
• Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics
• Immunoglobulin J Recombination Signal Sequence-Binding Protein/immunology
• Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
• Interleukin-17/immunology
• Interleukin-17/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Multiple Sclerosis/immunology
• Oligodendrocyte Precursor Cells/physiology
• Primary Cell Culture
• Protein Binding/immunology
• Protein Domains/physiology
• Receptor, Notch1/genetics
• Receptor, Notch1/immunology
• Receptor, Notch1/metabolism
• Receptors, Interleukin-17/metabolism
• Remyelination/physiology
• Signal Transduction/immunology
• Th1 Cells/immunology
• Th17 Cells/immunology
• Th17 Cells/metabolism
• Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism

• R01 NS071996 NINDS NIH HHS
• P01 HL029582 NHLBI NIH HHS
• U10 HL109250 NHLBI NIH HHS
• P01 HL103453 NHLBI NIH HHS
• P01 CA062220 NCI NIH HHS

Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination. Here, we show that members of the Kpna family regulate OL differentiation, and may play distinct roles downstream of different pro-myelinating stimuli. Multiple family members are expressed in OLs, and their pharmacologic inactivation dose-dependently decreases the rate of differentiation. Additionally, upon differentiation, the three major Kpna subtypes (P/α2, Q/α3, S/α1) display differential responses to the pro-myelinating cues T3 and CNTF. Most notably, the Q/α3 karyopherin Kpna4 is strongly upregulated by CNTF treatment both compared with T3 treatment and other Kpna responses. Kpna4 inactivation results in inhibition of CNTF-induced OL differentiation, in the absence of changes in proliferation or viability. Collectively, these findings suggest that canonical nuclear import is an integral component of OL differentiation, and that specific Kpnas may serve vital and distinct functions downstream of different pro-myelinating cues.

• Animals
• Cell Differentiation/physiology
• Cell Line
• Gene Expression Profiling
• Gene Expression Regulation, Developmental/physiology
• Mice
• Oligodendroglia/physiology
• Stem Cells/physiology
• alpha Karyopherins/physiology

• F30 NS090718 NINDS NIH HHS
• R01 NS062703 NINDS NIH HHS
• R01 NS085103 NINDS NIH HHS
• R24 CA095823 NCI NIH HHS
• National Institute of Neurological Disorders and Stroke
• National Multiple Sclerosis Society
• Beker Foundation
• Noto Foundation
• Guthy-Jackson Charitable Foundation

• Animals
• Autistic Disorder/genetics
• Carrier Proteins/metabolism
• Cell Line
• Cell Nucleus/metabolism
• Gene Knockdown Techniques
• Genetic Association Studies
• Humans
• Membrane Proteins
• Mice
• Nerve Tissue Proteins/metabolism
• Nuclear Localization Signals/metabolism
• Protein Binding
• Protein Structure, Tertiary
• Protein Transport
• Receptor, Notch1/chemistry
• Receptor, Notch1/metabolism
• Transcription, Genetic
• Two-Hybrid System Techniques

Glioma is an aggressive malignancy with limited effective treatment and poor prognosis. Therefore, the identification of novel prognostic markers and effective therapeutic targets is important for the treatment of human glioma. TIP30 is a tumor suppressor involved in the regulation of numerous cellular processes, including tumor cell growth, metastasis, and angiogenesis in various human cancers. The present study investigated whether Tat-interacting protein (TIP)30 was able to regulate tumorigenesis and predict the clinical outcome of patients with glioma. A total of 92 human glioma tissue samples and 10 normal brain tissue samples were examined by immunostaining. The results indicated that the expression levels of TIP30 significantly decreased in glioma tissue samples. as compared with normal brain tissue samples. Furthermore, TIP30 expression was inversely correlated with tumor histological classification, pathological grade, tumor size, and epidermal growth factor receptor (EGFR) expression; however, no association was detected between TIP30 expression and patient age and gender. In addition, patients with positive TIP30 expression exhibited significantly longer median overall survival rates, as compared with those with negative TIP30 expression. In vitro experiments revealed that upregulation of TIP30 expression by lentiviral vector transfection inhibited cell growth and induced cell apoptosis, as determined by MTT assay and Annexin V-fluorescein isothiocyanate staining, respectively. In addition, TIP30 expression markedly attenuated cell migration and invasion, as determined by wound healing and transwell assays. Upregulation of TIP30 expression in glioma cells decreased the expression levels of EGFR and its associated downstream molecules phosphorylated extracellular signal-regulated kinases (ERK) and phosphorylated AKT, as determined by western blot analysis. The results of the present study indicated that TIP30 may suppress oncogenesis and glioma progression, thereby improving the prognosis of patients with glioma. Therefore, TIP30 may prove useful as a prognostic biomarker, and as a potential target for glioma therapy.

• Lamin B1
• chromatin
• demyelination
• gene expression
• inflammation
• lipid

• Aging/genetics
• Aging/metabolism
• Animals
• Demyelinating Diseases/genetics
• Demyelinating Diseases/metabolism
• Gene Expression Regulation
• Humans
• Lamin Type B/biosynthesis
• Lipid Metabolism/physiology
• Mice
• Mice, Transgenic
• Nuclear Lamina/genetics
• Nuclear Lamina/metabolism
• Oligodendroglia/metabolism

• CA153114 NCI NIH HHS
• P30 CA047904 NCI NIH HHS
• P30CA047904 NCI NIH HHS
• R21AG046897 NIA NIH HHS
• R37 NS042925 NINDS NIH HHS
• UL1 TR000005 NCATS NIH HHS
• R21 CA153114 NCI NIH HHS
• R37NS04295 NINDS NIH HHS
• R21 AG046897 NIA NIH HHS

A prominent feature of demyelinating diseases such as multiple sclerosis (MS) is the degeneration and loss of previously established functional myelin sheaths, which results in impaired signal propagation and axonal damage. However, at least in early disease stages, partial replacement of lost oligodendrocytes and thus remyelination occur as a result of resident oligodendroglial precursor cell (OPC) activation. These cells represent a widespread cell population within the adult central nervous system (CNS) that can differentiate into functional myelinating glial cells to restore axonal functions. Nevertheless, the spontaneous remyelination capacity in the adult CNS is inefficient because OPCs often fail to generate new oligodendrocytes due to the lack of stimulatory cues and the presence of inhibitory factors. Recent studies have provided evidence that regulated intracellular protein shuttling is functionally involved in oligodendroglial differentiation and remyelination activities. In this review we shed light on the role of the subcellular localization of differentiation-associated factors within oligodendroglial cells and show that regulation of intracellular localization of regulatory factors represents a crucial process to modulate oligodendroglial maturation and myelin repair in the CNS.

• differentiation inhibitors
• multiple sclerosis
• myelin repair
• nucleocytoplasmic shuttling
• oligodendrocyte
• remyelination
• transcription factors

Since disability in multiple sclerosis (MS) is a product of neurodegeneration and deficient remyelination, the ability to enhance neuroregeneration and myelin regeneration in MS is an enticing goal for MS drug development. In particular, remyelination treatments could promote return of neurological function and also prevent further axonal loss and neurodegeneration in MS due to trophic effects of myelin. The study of remyelination has advanced dramatically in the last several years such that a number of pathways inhibiting remyelination have been discovered, including those involving LINGO-1, Notch-1, hyaluronan, retinoid X receptor, and wnt/ß-catenin. Other approaches such as high throughput drug screening for remyelination drugs have caught fire, with identification of dozens of known drugs with oligodendrocyte maturation stimulatory effects. Several drugs identified through screens and other mechanisms are in the process of being further evaluated for remyelination in MS and MS models. We discuss the potential molecular targets and the variety of mechanisms towards drug identification and development in remyelination for MS.

• Multiple sclerosis
• Myelin
• Remyelination
• Oligodendrocyte
• Repurposing
• Treatment

• inhibitor
• mode of action
• myelin repair
• nuclear export
• p57kip2
• regeneration

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions.

• gliogenesis
• multiple sclerosis
• neural stem cells
• neurogenesis
• therapy

Reports that chronically demyelinated multiple sclerosis brain and spinal cord lesions contained immature oligodendrocyte lineage cells have generated major interest aimed at the potential for promotion of endogenous repair. Despite the prominence of the optic nerve as a lesion site and its importance in clinical disease assessment, no detailed studies of multiple sclerosis‐affected optic nerve exist. This study aims to provide insight into the cellular pathology of chronic demyelination in multiple sclerosis through direct morphological and immunohistochemical analysis of optic nerve in conjunction with observations from an experimental cat optic nerve model of successful remyelination. Myelin staining was followed by immunohistochemistry to differentially label neuroglia. Digitally immortalized sections were then analyzed to generate quantification data and antigenic phenotypes including maturational stages within the oligodendrocyte lineage. It was found that some chronically demyelinated multiple sclerosis optic nerve lesions contained oligodendroglial cells and that heterogeneity existed in the presence of myelin sheaths, oligodendrocyte maturational stages and extent of axonal investment. The findings advance our understanding of oligodendrocyte activity in chronically demyelinated human optic nerve and may have implications for studies aimed at enhancement of endogenous repair in multiple sclerosis.

• chronic demyelination
• multiple sclerosis
• oligodendrocytes
• optic nerve
• remyelination failure

Laryngeal squamous cell carcinoma (LSCC) is one of the most common carcinomas of the head and neck. Despite advances in diagnosis and treatment, the survival of patients with LSCC has not improved in the past two decades. TIP30, a newly identified tumour suppressor, appears to be involved in multiple processes during tumour development. Here, we investigated the involvement of TIP30 in chemoresistance of LSCC in vitro and in vivo. We showed that TIP30 expression decreased significantly in drug-selected cells (DSCs) of laryngeal carcinoma. Suppressing TIP30 enhanced resistance capability to multiple chemotherapy drugs, cell proliferation and self-renewal in Hep2 cells. Additionally, decreased self-renewal capacity and chemotherapeutic resistance were observed in DSCs overexpressing TIP30. Furthermore, TIP30 negatively regulated tumourigenesis and chemoresistance in LSCC cells subcutaneously transplanted into nude mice. Moreover, decreased TIP30 expression contributed to chemoresistance, self-renewal and proliferation of LSCC cells via nuclearlisation of β-catenin, a cell–cell adhesion and stem cell renewal regulator. Consistently, Kaplan–Meier and Cox proportional hazards regression modelling analyses showed that decreased TIP30 expression independently predicted poor survival in patients with LSCC. Taken together, our results reveal that TIP30 has a crucial role in chemoresistance of LSCC through the AKT/glycogen synthase kinase-3β/β-catenin signalling pathway and may be a promising candidate for improving LSCC chemotherapy.

White matter dysfunction is an important part of many CNS disorders including multiple sclerosis (MS) and vascular dementia. Within injured areas, myelin loss and oligodendrocyte death may trigger endogenous attempts at regeneration. However, during disease progression, remyelination failure may eventually occur due to impaired survival/proliferation, migration/recruitment, and differentiation of oligodendrocyte precursor cells (OPCs). The ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) are the main sources of neural stem/progenitor cells (NSPCs), which can give rise to neurons as well as OPCs. Under normal conditions in the adult brain, the V-SVZ progenitors generate a large number of neurons with a small number of oligodendrocyte lineage cells. However, after demyelination, the fate of V-SVZ-derived progenitor cells shifts from neurons to OPCs, and these newly generated OPCs migrate to the demyelinating lesions to ease white matter damage. In this mini-review, we will summarize the recent studies on extrinsic (e.g., vasculature, extracellular matrix (ECM), cerebrospinal fluid (CSF)) and intrinsic (e.g., transcription factors, epigenetic modifiers) factors, which mediate oligodendrocyte generation from the V-SVZ progenitor cells. A deeper understanding of the mechanisms that regulate the fate of V-SVZ progenitor cells may lead to new therapeutic approaches for ameliorating white matter dysfunction and damage in CNS disorders.

• demyelination
• multiple sclerosis
• neural stem/progenitor cells
• oligodendrocyte precursor cells
• oligodendrogenesis
• subventricular zone
• vascular dementia

• Axonal damage
• Epigenetics
• Multiple sclerosis
• Neurodegeneration
• Repair
• Therapy
• myelin

Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8⁺, NKT, CD4⁺CD25⁺ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination—with emphasis upon myelin composition/architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

• amyotrophic lateral sclerosis
• hypoxia-inducible factor-1α
• impaired cytoplasmic-nuclear transport
• mutant superoxide dismutase 1
• vascular endothelial growth factor

• oligodendrocytes
• myelin
• demyelination
• remyelination
• multiple sclerosis

• Animals
• Demyelinating Diseases/drug therapy
• Demyelinating Diseases/pathology
• Humans
• Immunologic Factors/therapeutic use
• Multiple Sclerosis/drug therapy
• Multiple Sclerosis/pathology
• Myelin Sheath/drug effects
• Myelin Sheath/pathology

• Animals
• Autoimmune Diseases/immunology
• Autoimmunity/immunology
• Humans
• Multiple Sclerosis/immunology
• Multiple Sclerosis/pathology
• Oligodendroglia/pathology

• notch
• pleiotropy
• dominant syndrome
• cadasil

• Alagille Syndrome/genetics
• Alagille Syndrome/metabolism
• Animals
• Bone Diseases, Metabolic/genetics
• Bone Diseases, Metabolic/metabolism
• CADASIL/genetics
• CADASIL/metabolism
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/metabolism
• Genetic Pleiotropy
• Humans
• Mutation
• Neoplasms/genetics
• Oncogenes
• Receptors, Notch/genetics
• Receptors, Notch/metabolism
• Receptors, Notch/physiology
• Signal Transduction/genetics

• R01 CA098402 NCI NIH HHS

• adam
• cadasil
• γ-secretase
• multiple sclerosis
• notch
• t-all
• stem cell
• tissue renewal

• ADAM Proteins/metabolism
• Amyloid Precursor Protein Secretases/metabolism
• Animals
• Cell Communication
• Humans
• Models, Biological
• Receptors, Notch/metabolism
• Signal Transduction/physiology
• Wounds and Injuries/metabolism

• P50 AG05681 NIA NIH HHS
• P50 AG005681 NIA NIH HHS
• GM55479 NIGMS NIH HHS
• R01 GM055479 NIGMS NIH HHS
• R01 AG025973 NIA NIH HHS
• AG025973 NIA NIH HHS

• cytokines
• chemokines
• growth factors
• microrna
• multiple sclerosis
• transcription factors

• Animals
• Cell Differentiation
• Chemokines/metabolism
• Humans
• MicroRNAs/metabolism
• Myelin Sheath/metabolism
• Oligodendroglia/cytology
• Oligodendroglia/metabolism
• Signal Transduction
• Transcription Factors/metabolism

• P01 NS059560 NINDS NIH HHS
• R01 NS052632 NINDS NIH HHS
• NS059560 NINDS NIH HHS

• multiple sclerosis
• remyelination
• stem cell
• regenerative medicine

• Animals
• Central Nervous System/cytology
• Central Nervous System/metabolism
• Humans
• Multiple Sclerosis/physiopathology
• Multiple Sclerosis/therapy
• Myelin Sheath/metabolism
• Nerve Regeneration/drug effects
• Nerve Regeneration/physiology
• Stem Cells/physiology

• G0800784 Medical Research Council

• multiple sclerosis, stem cell, transplantation, remyelination, immunomodulation.

• Cell Transplantation/methods
• Embryonic Stem Cells/physiology
• Humans
• Immunomodulation/physiology
• Multiple Sclerosis/immunology
• Multiple Sclerosis/surgery
• Myelin Proteins/immunology
• Myelin Proteins/metabolism
• Stem Cell Transplantation/methods

• Analysis of Variance
• Animals
• Animals, Newborn
• Cell Differentiation/drug effects
• Cell Differentiation/physiology
• Female
• Immunohistochemistry
• In Situ Hybridization
• Myelin Sheath/drug effects
• Myelin Sheath/metabolism
• Myelin Sheath/pathology
• Nerve Regeneration/physiology
• Oligodendroglia/drug effects
• Oligodendroglia/metabolism
• Oligodendroglia/pathology
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Semaphorin-3A/metabolism
• Semaphorin-3A/pharmacology

• G0800784 Medical Research Council

• multiple sclerosis
• ms
• oligodendrocyte
• neuroprotection
• remyelination
• repair

• Animals
• Autoimmunity/drug effects
• Axons/drug effects
• Axons/metabolism
• Axons/pathology
• Encephalomyelitis, Autoimmune, Experimental
• Gene Regulatory Networks/immunology
• Humans
• Immunologic Factors/metabolism
• Immunologic Factors/therapeutic use
• Inflammation/drug therapy
• Inflammation/metabolism
• Inflammation/pathology
• Molecular Targeted Therapy
• Multiple Sclerosis/drug therapy
• Multiple Sclerosis/genetics
• Multiple Sclerosis/pathology
• Multiple Sclerosis/physiopathology
• Myelin Sheath/metabolism
• Myelin Sheath/pathology
• Neuroprotective Agents/therapeutic use
• Oligodendroglia/drug effects
• Oligodendroglia/metabolism
• Oligodendroglia/pathology
• Spinal Cord Regeneration/drug effects
• Spinal Cord Regeneration/immunology
• Therapies, Investigational

• T32 NS051147 NINDS NIH HHS
• T32NS051147-03 NINDS NIH HHS
• R01 NS056074 NINDS NIH HHS
• R01 NS046620 NINDS NIH HHS
• R01 NS062703 NINDS NIH HHS