Role of PARP1 in oligodendrocyte differentiation during developmental myelination and remyelination after myelin damage

AbstractThe function of poly(ADP-ribosyl) polymerase 1 (PARP1) in myelination and remyelination of the central nervous system (CNS) remain enigmatic. Here we report that PARP1 is an intrinsic driver for oligodendroglial development and myelination. Genetic PARP1 depletion impairs the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and impedes CNS myelination. Mechanistically, PARP1-mediated PARylation activity is not only necessary but also sufficient for OPC differentiation. At the molecular level, we identify the RNA-binding protein Myef2 as a novel PARylated target which we show controls OPC differentiation through PARylation-modulated de-repression of myelin protein expression. Furthermore, PARP1’s enzymatic activity is necessary for oligodendrocyte and myelin regeneration after demyelination. Together, our findings suggest that PARP1-mediated PARylation activity may be a potential therapeutic target for promoting OPC differentiation and remyelination in neurological disorders characterized by arrested OPC differentiation and remyelination failure such as multiple sclerosis.

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A Role of Microtubules in Oligodendrocyte Differentiation

International Journal of Molecular Sciences ◽

10.3390/ijms21031062 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1062

Author(s):

Bo Yoon Lee ◽

Eun-Mi Hur

Keyword(s):

Neurological Disorders ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Differentiation ◽

Epothilone B ◽

Myelin Sheaths ◽

Simple Protocol ◽

The Central Nervous System ◽

Central Nervous System Defects ◽

Late Stages

Oligodendrocytes are specialized cells that myelinate axons in the central nervous system. Defects in oligodendrocyte function and failure to form or maintain myelin sheaths can cause a number of neurological disorders. Oligodendrocytes are differentiated from oligodendrocyte progenitor cells (OPCs), which extend several processes that contact, elaborate, and eventually wrap axonal segments to form multilayered myelin sheaths. These processes require extensive changes in the cytoarchitecture and must be regulated by reorganization of the cytoskeleton. Here, we established a simple protocol to isolate and differentiate mouse OPCs, and by using this method, we investigated a role of microtubules (MTs) in oligodendrocyte differentiation. Oligodendrocytes developed a complex network of MTs during differentiation, and treatment of differentiating oligodendrocytes with nanomolar concentrations of MT-targeting agents (MTAs) markedly affected oligodendrocyte survival and differentiation. We found that acute exposure to vincristine and nocodazole at early stages of oligodendrocyte differentiation markedly increased MT arborization and enhanced differentiation, whereas taxol and epothilone B treatment produced opposing outcomes. Furthermore, treatment of myelinating co-cultures of oligodendrocytes and neurons with nanomolar concentrations of MTAs at late stages of oligodendrocyte differentiation induced dysmyelination. Together, these results suggest that MTs play an important role in the survival, differentiation, and myelination of oligodendrocytes.

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Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis

Cell Death and Disease ◽

10.1038/s41419-021-03671-2 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Shanshan Liu ◽

Xiuxin Jiang ◽

Xiuru Cui ◽

Jingjing Wang ◽

Shangming Liu ◽

...

Keyword(s):

Smooth Muscle ◽

Cardiovascular Events ◽

Rna Binding ◽

Rna Binding Protein ◽

Plaque Burden ◽

Atherosclerotic Plaques ◽

Ampk Activation ◽

Homeostatic Regulation ◽

Human Antigen R

AbstractHuman antigen R (HuR) is a widespread RNA-binding protein involved in homeostatic regulation and pathological processes in many diseases. Atherosclerosis is the leading cause of cardiovascular disease and acute cardiovascular events. However, the role of HuR in atherosclerosis remains unknown. In this study, mice with smooth muscle-specific HuR knockout (HuRSMKO) were generated to investigate the role of HuR in atherosclerosis. HuR expression was reduced in atherosclerotic plaques. As compared with controls, HuRSMKO mice showed increased plaque burden in the atherosclerotic model. Mechanically, HuR could bind to the mRNAs of adenosine 5′-monophosphate-activated protein kinase (AMPK) α1 and AMPKα2, thus increasing their stability and translation. HuR deficiency reduced p-AMPK and LC3II levels and increased p62 level, thereby resulting in defective autophagy. Finally, pharmacological AMPK activation induced autophagy and suppressed atherosclerosis in HuRSMKO mice. Our findings suggest that smooth muscle HuR has a protective effect against atherosclerosis by increasing AMPK-mediated autophagy.

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Intestinal Microbiota as an Alternative Therapeutic Target for Epilepsy

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2016/9032809 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 12

Author(s):

Jiaying Wu ◽

Yuyu Zhang ◽

Hongyu Yang ◽

Yuefeng Rao ◽

Jing Miao ◽

...

Keyword(s):

Immune Responses ◽

Intestinal Microbiota ◽

Neurological Disorders ◽

Digestive System ◽

Hygiene Hypothesis ◽

Host Susceptibility ◽

Immune Disorders ◽

The Central Nervous System ◽

Symbiotic Microbiota

Epilepsy is one of the most widespread serious neurological disorders, and an aetiological explanation has not been fully identified. In recent decades, a growing body of evidence has highlighted the influential role of autoimmune mechanisms in the progression of epilepsy. The hygiene hypothesis draws people’s attention to the association between gut microbes and the onset of multiple immune disorders. It is also believed that, in addition to influencing digestive system function, symbiotic microbiota can bidirectionally and reversibly impact the programming of extraintestinal pathogenic immune responses during autoimmunity. Herein, we investigate the concept that the diversity of parasitifer sensitivity to commensal microbes and the specific constitution of the intestinal microbiota might impact host susceptibility to epilepsy through promotion of Th17 cell populations in the central nervous system (CNS).

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Critical role of tristetraprolin and AU‐rich element RNA‐binding protein 1 in the suppression of cancer cell growth by globular adiponectin

FEBS Open Bio ◽

10.1002/2211-5463.12541 ◽

2018 ◽

Vol 8 (12) ◽

pp. 1964-1976 ◽

Cited By ~ 1

Author(s):

Nirmala Tilija Pun ◽

Amrita Khakurel ◽

Aastha Shrestha ◽

Sang‐Hyun Kim ◽

Pil‐Hoon Park

Keyword(s):

Cell Growth ◽

Cancer Cell ◽

Rna Binding ◽

Binding Protein ◽

Critical Role ◽

Rna Binding Protein ◽

Cancer Cell Growth ◽

Globular Adiponectin

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The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

Biochemical Society Transactions ◽

10.1042/bst20160166 ◽

2016 ◽

Vol 44 (5) ◽

pp. 1321-1337 ◽

Cited By ~ 39

Author(s):

Andrew R. Clark ◽

Jonathan L.E. Dean

Keyword(s):

Inflammatory Mediators ◽

Knockout Mouse ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Human Orthologue ◽

And Function ◽

Detailed Picture ◽

Lines Of Evidence

Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.

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Deficiency of T-Cell Intracellular Antigen 1 in Murine Embryonic Fibroblasts Is Associated with Changes in Mitochondrial Morphology and Respiration

International Journal of Molecular Sciences ◽

10.3390/ijms222312775 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12775

Author(s):

Isabel Carrascoso ◽

Beatriz Ramos Velasco ◽

José M. Izquierdo

Keyword(s):

T Cell ◽

Rna Binding ◽

Mitochondrial Dynamics ◽

Rna Binding Protein ◽

Mitochondrial Morphology ◽

Embryonic Fibroblasts ◽

Intracellular Antigen ◽

Molecular Components ◽

Shed Light

T-cell intracellular antigen 1 (TIA1) is a multifunctional RNA-binding protein involved in regulating gene expression and splicing during development and in response to environmental stress, to maintain cell homeostasis and promote survival. Herein, we used TIA1-deficient murine embryonic fibroblasts (MEFs) to study their role in mitochondria homeostasis. We found that the loss of TIA1 was associated with changes in mitochondrial morphology, promoting the appearance of elongated mitochondria with heterogeneous cristae density and size. The proteomic patterns of TIA1-deficient MEFs were consistent with expression changes in molecular components related to mitochondrial dynamics/organization and respiration. Bioenergetics analysis illustrated that TIA1 deficiency enhances mitochondrial respiration. Overall, our findings shed light on the role of TIA1 in mitochondrial dynamics and highlight a point of crosstalk between potential pro-survival and pro-senescence pathways.

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Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.789834 ◽

2021 ◽

Vol 13 ◽

Author(s):

Banglian Hu ◽

Shengshun Duan ◽

Ziwei Wang ◽

Xin Li ◽

Yuhang Zhou ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurological Disorders ◽

Neurological Diseases ◽

Colony Stimulating Factor ◽

Loss Of Function ◽

Axonal Spheroids ◽

The Central Nervous System ◽

Stimulating Factor

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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