scholarly journals Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xin Zhou ◽  
Seula Shin ◽  
Chenxi He ◽  
Qiang Zhang ◽  
Matthew N Rasband ◽  
...  
Keyword(s):  
Rna Binding ◽  
Cholesterol Biosynthesis ◽  
Oligodendrocyte Precursor Cells ◽  
Canonical Function ◽  
Oligodendrocyte Differentiation ◽  
Precise Control ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Underlying Mechanisms ◽  
Myelin Assembly

Myelination depends on timely, precise control of oligodendrocyte differentiation and myelinogenesis. Cholesterol is the most abundant component of myelin and essential for myelin membrane assembly in the central nervous system. However, the underlying mechanisms of precise control of cholesterol biosynthesis in oligodendrocytes remain elusive. In the present study, we found that Qki depletion in neural stem cells or oligodendrocyte precursor cells in neonatal mice resulted in impaired cholesterol biosynthesis and defective myelinogenesis without compromising their differentiation into Aspa+Gstpi+ myelinating oligodendrocytes. Mechanistically, Qki-5 functions as a co-activator of Srebp2 to control transcription of the genes involved in cholesterol biosynthesis in oligodendrocytes. Consequently, Qki depletion led to substantially reduced concentration of the cholesterol in mouse brain, impairing proper myelin assembly. Our study demonstrated that Qki-Srebp2–controlled cholesterol biosynthesis is indispensable for myelinogenesis and highlights a novel function of Qki as a transcriptional co-activator beyond its canonical function as an RNA-binding protein.

scholarly journals White Matter and Neuroprotection in Alzheimer’s Dementia

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 503 ◽  
Author(s):  
Luca Lorenzini ◽  
Mercedes Fernandez ◽  
Vito Antonio Baldassarro ◽  
Andrea Bighinati ◽  
Alessandro Giuliani ◽  
...  
Keyword(s):  
White Matter ◽  
Alzheimer’S Dementia ◽  
Oligodendrocyte Precursor Cells ◽  
Resonance Imaging ◽  
Alzheimer's Dementia ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Main Component ◽  
Preclinical And Clinical Studies

Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer’s dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.

scholarly journals Microglial ASD-related genes are involved in oligodendrocyte differentiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuta Takanezawa ◽  
Shogo Tanabe ◽  
Daiki Kato ◽  
Rie Ozeki ◽  
Masayo Komoda ◽  
...  
Keyword(s):  
Autism Spectrum ◽  
Oligodendrocyte Precursor Cells ◽  
Oligodendrocyte Differentiation ◽  
Spectrum Disorders ◽  
Oligodendrocyte Precursor ◽  
Oligodendrocyte Development ◽  
Igf1 Expression ◽  
Phagocytosis Activity

AbstractAutism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.

scholarly journals The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Khalil S. Rawji ◽  
V. Wee Yong
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Neurotrophic Factors ◽  
Neurological Diseases ◽  
Oligodendrocyte Precursor Cells ◽  
Activated Macrophages ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Experimental Autoimmune

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.

scholarly journals A Matter of State: Diversity in Oligodendrocyte Lineage Cells

2021 ◽  
pp. 107385842098720
Author(s):  
Yasmine Kamen ◽  
Helena Pivonkova ◽  
Kimberley A. Evans ◽  
Ragnhildur T. Káradóttir
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adult Brain ◽  
Developmental Origins ◽  
Oligodendrocyte Precursor Cells ◽  
Homogeneous Population ◽  
Physiological Properties ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Transcriptome Response

Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes which myelinate axons in the central nervous system. Although classically thought to be a homogeneous population, OPCs are reported to have different developmental origins and display regional and temporal diversity in their transcriptome, response to growth factors, and physiological properties. Similarly, evidence is accumulating that myelinating oligodendrocytes display transcriptional heterogeneity. Analyzing this reported heterogeneity suggests that OPCs, and perhaps also myelinating oligodendrocytes, may exist in different functional cell states. Here, we review the evidence indicating that OPCs and oligodendrocytes are diverse, and we discuss the implications of functional OPC states for myelination in the adult brain and for myelin repair.

scholarly journals Connecting Neuroinflammation and Neurodegeneration in Multiple Sclerosis: Are Oligodendrocyte Precursor Cells a Nexus of Disease?

2021 ◽  
Vol 15 ◽  
Author(s):  
Morgan W. Psenicka ◽  
Brandon C. Smith ◽  
Rachel A. Tinkey ◽  
Jessica L. Williams
Keyword(s):  
Multiple Sclerosis ◽  
Animal Models ◽  
Active Role ◽  
Precursor Cells ◽  
Oligodendrocyte Precursor Cells ◽  
Secreted Factors ◽  
Autoimmune Pathology ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
The Impact

The pathology in neurodegenerative diseases is often accompanied by inflammation. It is well-known that many cells within the central nervous system (CNS) also contribute to ongoing neuroinflammation, which can promote neurodegeneration. Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease in which there is a complex interplay between resident CNS cells to mediate myelin and axonal damage, and this communication network can vary depending on the subtype and chronicity of disease. Oligodendrocytes, the myelinating cell of the CNS, and their precursors, oligodendrocyte precursor cells (OPCs), are often thought of as the targets of autoimmune pathology during MS and in several animal models of MS; however, there is emerging evidence that OPCs actively contribute to inflammation that directly and indirectly contributes to neurodegeneration. Here we discuss several contributors to MS disease progression starting with lesion pathology and murine models amenable to studying particular aspects of disease. We then review how OPCs themselves can play an active role in promoting neuroinflammation and neurodegeneration, and how other resident CNS cells including microglia, astrocytes, and neurons can impact OPC function. Further, we outline the very complex and pleiotropic role(s) of several inflammatory cytokines and other secreted factors classically described as solely deleterious during MS and its animal models, but in fact, have many neuroprotective functions and promote a return to homeostasis, in part via modulation of OPC function. Finally, since MS affects patients from the onset of disease throughout their lifespan, we discuss the impact of aging on OPC function and CNS recovery. It is becoming clear that OPCs are not simply a bystander during MS progression and uncovering the active roles they play during different stages of disease will help uncover potential new avenues for therapeutic intervention.

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