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Myelin gene regulatory factor

Zhimin Ou, Yuxia Sun, Li Lin, Nachun You, Xue Liu, Hongchao Li, Yanchen Ma, Lei Cao, Ying Han, Min Liu, Yaqi Deng, Luming Yao, Q Richard Lu, Ying Chen
: Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus...
October 12, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Vidar M Steen, Silje Skrede, Tatiana Polushina, Miguel López, Ole A Andreassen, Johan Fernø, Stephanie Le Hellard
Schizophrenia is a serious psychotic disorder, with disabling symptoms and markedly reduced life expectancy. The onset is usually in late adolescence or early adulthood, which in time overlaps with the maturation of the brain including the myelination process. Interestingly, there seems to be a link between myelin abnormalities and schizophrenia. The oligodendrocyte-derived myelin membranes in the CNS are highly enriched for lipids (cholesterol, phospholipids and glycosphingolipids), thereby pointing at lipid homeostasis as a relevant target for studying the genetics and pathophysiology of schizophrenia...
August 1, 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Elizabeth A Fogarty, Megan H Brewer, Jose F Rodriguez-Molina, William D Law, Ki H Ma, Noah M Steinberg, John Svaren, Anthony Antonellis
Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves...
July 27, 2016: Human Molecular Genetics
Yoshifumi Ashikawa, Yuhei Nishimura, Shiko Okabe, Shota Sasagawa, Soichiro Murakami, Mizuki Yuge, Koki Kawaguchi, Reiko Kawase, Toshio Tanaka
Oligodendrocytes are major myelin-producing cells and play essential roles in the function of a healthy nervous system. However, they are also one of the most vulnerable neural cell types in the central nervous system (CNS), and myelin abnormalities in the CNS are found in a wide variety of neurological disorders, including multiple sclerosis, adrenoleukodystrophy, and schizophrenia. There is an urgent need to identify small molecular weight compounds that can stimulate myelination. In this study, we performed comparative transcriptome analysis to identify pharmacodynamic effects common to miconazole and clobetasol, which have been shown to stimulate myelination by mouse oligodendrocyte progenitor cells (OPCs)...
2016: Frontiers in Pharmacology
Jun Li, Yanbin Liu, Haidong Xu, Qiang Fu
Macrophage activation and persistent inflammation contribute to the pathogenesis of spinal cord injury (SCI), and different phenotypes of macrophages play diverse roles in the pathological process of SCI. After SCI, there is an acute phase of alternatively activated (M2) macrophage infiltration, followed by a long-lasting phase of classically activated (M1) macrophage accumulation in the wound. The long-lasting predominance of M1 macrophages may derail healing and compromise organ functions. Based on the previous findings that the transcription factor interferon regulatory factor 5 (IRF5) up-regulates genes associated with M1 macrophages, we attempted to examine the effect of silencing IRF5 on SCI progression...
October 2016: Inflammation
Hubert Monnerie, Micah Romer, Brigid K Jensen, John S Millar, Kelly L Jordan-Sciutto, Sangwon F Kim, Judith B Grinspan
The formation of the myelin membrane of the oligodendrocyte in the CNS is a fundamental process requiring the coordinated synthesis of many different components. The myelin membrane is particularly rich in lipids, however, the regulation of these synthesis of these is not understood. In other cell types, including Schwann cells, the myelin-forming cells of the PNS, lipid synthesis is tightly regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors, but this has not been previously shown in oligodendrocytes...
July 6, 2016: Journal of Neurochemistry
Xiu-Mei Xie, Ling-Ling Shi, Lin Shen, Rui Wang, Qi Qi, Qi-Yi Wang, Lun-Jun Zhang, He-Zuo Lü, Jian-Guo Hu
Oligodendrocyte (OL) replacement is a promising treatment strategy for spinal cord injury (SCI). However, the poor survival of transplanted OLs or their precursors and inhibition of axonal regeneration are two major challenges with this approach. Our previous study showed that Schwann cells (SCs) promoted survival, proliferation, and migration of transplanted OL progenitor cells (OPCs) and neurological recovery. Remyelination is an important basis for functional recovery following spinal cord injury. It has been reported that myelin gene regulatory factor (MRF), a transcriptional regulator which specifically is expressed in postmitotic OLs within the CNS, is essential for OL maturation and CNS myelination...
October 2016: Neurobiology of Disease
Ewa Kozela, Ana Juknat, Fuying Gao, Nathali Kaushansky, Giovanni Coppola, Zvi Vogel
BACKGROUND: Our previous studies showed that the non-psychoactive cannabinoid, cannabidiol (CBD), ameliorates the clinical symptoms in mouse myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis model of multiple sclerosis (MS) as well as decreases the memory MOG35-55-specific T cell (TMOG) proliferation and cytokine secretion including IL-17, a key autoimmune factor. The mechanisms of these activities are currently poorly understood. METHODS: Herein, using microarray-based gene expression profiling, we describe gene networks and intracellular pathways involved in CBD-induced suppression of these activated memory TMOG cells...
2016: Journal of Neuroinflammation
Danyang He, Corentine Marie, Chuntao Zhao, Bongwoo Kim, Jincheng Wang, Yaqi Deng, Adrien Clavairoly, Magali Frah, Haibo Wang, Xuelian He, Hatem Hmidan, Blaise V Jones, David Witte, Bernard Zalc, Xin Zhou, Daniel I Choo, Donna M Martin, Carlos Parras, Q Richard Lu
Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes...
May 2016: Nature Neuroscience
Bing Gong, Miroslav Radulovic, Maria E Figueiredo-Pereira, Christopher Cardozo
The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes. Herein, we will review advances in the understanding of the role of several proteins of the UPS in Alzheimer's disease (AD) and functional recovery after spinal cord injury (SCI). The UPS consists of many factors that include E3 ubiquitin ligases, ubiquitin hydrolases, ubiquitin and ubiquitin-like molecules, and the proteasome itself. An extensive body of work links UPS dysfunction with AD pathogenesis and progression...
2016: Frontiers in Molecular Neuroscience
Jellert T Gaublomme, Nir Yosef, Youjin Lee, Rona S Gertner, Li V Yang, Chuan Wu, Pier Paolo Pandolfi, Tak Mak, Rahul Satija, Alex K Shalek, Vijay K Kuchroo, Hongkun Park, Aviv Regev
Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions...
December 3, 2015: Cell
Jianbin Zhong, Shengnuo Fan, Zhenwen Yan, Songhua Xiao, Limei Wan, Chibang Chen, Simin Zhong, Lu Liu, Jun Liu
Parkinson's disease (PD) is a common degenerative disease that lacks efficient treatment. Myelin-associated neurite outgrowth inhibitor A (Nogo-A) is relevant with inhibition of nerve regeneration and may play vital role in pathogenesis of PD. The study aimed to establish the shRNA expression plasmids of Nogo-A gene and explore the regulatory effects of Nogo-A silencing on the expression of inflammation factor tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) as well as tyrosine hydroxylase (TH) in lipopolysaccharide- (LPS-) stimulated rat PC12 cells...
2015: BioMed Research International
Monika Burns, Sureshkumar Muthupalani, Zhongming Ge, Timothy C Wang, Vasudevan Bakthavatchalu, Catriona Cunningham, Kathleen Ennis, Michael Georgieff, James G Fox
Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world's population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS-GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6-9 weeks of age, and were necropsied at 27-29 weeks of age...
2015: PloS One
Yingjun Zhao, I-Chu Tseng, Charles J Heyser, Edward Rockenstein, Michael Mante, Anthony Adame, Qiuyang Zheng, Timothy Huang, Xin Wang, Pharhad E Arslan, Paramita Chakrabarty, Chengbiao Wu, Guojun Bu, William C Mobley, Yun-Wu Zhang, Peter St George-Hyslop, Eliezer Masliah, Paul Fraser, Huaxi Xu
Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation...
September 2, 2015: Neuron
Kristin D Kernohan, Martine Tétreault, Urszula Liwak-Muir, Michael T Geraghty, Wen Qin, Sunita Venkateswaran, Jorge Davila, Martin Holcik, Jacek Majewski, Julie Richer, Kym M Boycott
Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings...
November 15, 2015: Human Molecular Genetics
Justin A Spanier, Faye E Nashold, Christopher G Mayne, Corwin D Nelson, Colleen E Hayes
Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on the axon-myelin unit. A female MS bias becomes evident after puberty and female incidence has tripled in the last half-century, implicating a female sex hormone interacting with a modifiable environmental factor. These aspects of MS suggest that many female MS cases may be preventable. Mechanistic knowledge of this hormone-environment interaction is needed to devise strategies to reduce female MS risk. We previously demonstrated that vitamin D3 (D3) deficiency increases and D3 supplementation decreases experimental autoimmune encephalomyelitis (EAE) risk in a female-biased manner...
September 15, 2015: Journal of Neuroimmunology
Hsin-Pin Lin, Idil Oksuz, Edward Hurley, Lawrence Wrabetz, Rajeshwar Awatramani
We investigated the role of a key component of the Microprocessor complex, DGCR8, in the regulation of myelin formation and maintenance. We found that conditionally ablating Dgcr8 in Schwann cells (SCs) during development results in an arrest of SC differentiation. Dgcr8 conditional knock-out (cKO) SCs fail to form 1:1 relationships with axons or, having achieved this, fail to form myelin sheaths. The expression of genes normally found in immature SCs, such as sex-determining region Y-box 2 (Sox2), is increased in Dgcr8 cKO SCs, whereas the expression of myelin-related genes, including the master regulatory transcription factor early growth response 2 (Egr2), is decreased...
October 2, 2015: Journal of Biological Chemistry
Inna V Grishkan, Dominique M Tosi, Melissa D Bowman, Maya Harary, Peter A Calabresi, Anne R Gocke
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS that has been linked with defects in regulatory T cell function. Therefore, strategies to selectively target pathogenic cells via enhanced regulatory T cell activity may provide therapeutic benefit. Kv1.3 is a voltage-gated potassium channel expressed on myelin-reactive T cells from MS patients. Kv1.3-knockout (KO) mice are protected from experimental autoimmune encephalomyelitis, an animal model of MS, and Kv1.3-KO Th cells display suppressive capacity associated with increased IL-10...
August 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Ben Emery, Q Richard Lu
Central nervous system (CNS) myelination by oligodendrocytes (OLs) is a highly orchestrated process involving well-defined steps from specification of neural stem cells into proliferative OL precursors followed by terminal differentiation and subsequent maturation of these precursors into myelinating OLs. These specification and differentiation processes are mediated by profound global changes in gene expression, which are in turn subject to control by both extracellular signals and regulatory networks intrinsic to the OL lineage...
September 2015: Cold Spring Harbor Perspectives in Biology
Jui-Hung Yen, Weimin Kong, Kirsten M Hooper, Frances Emig, Kate M Rahbari, Ping-Chang Kuo, Barbara A Scofield, Doina Ganea
MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN-β, used clinically in RR-MS reduces lesion formation and rates of relapse. Although the molecular mechanisms are not entirely elucidated, myeloid cells appear to be a major target for the therapeutic effects of IFN-β. DCs have a critical role in experimental models of MS through their effect on encephalitogenic Th1/Th17 cell differentiation and expansion. Here we focused on the effects of IFN-β on DC expression of cytokines involved in the control of Th1/Th17 differentiation and expansion...
November 2015: Journal of Leukocyte Biology
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