Myelin and Oligodendrocyte Dysfunction in Demyelinating and Neurodegenerative Disorders: Signaling Pathways and Therapeutic Targets.

Myelin Alteration in Neurodevelopmental Disorders: Integrating Clinical and Preclinical Evidence.

The evidence suggests that myelin-related pathways represent a common point of vulnerability across disorders and may offer a potential target for intervention, integrating findings from both animal models and human research.

Crosstalk Between Oligodendrocyte Lineage Cells and CNS‐Resident and Peripheral Immune Cells Governs Demyelination and Remyelination in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease characterized by immune‐mediated attacks on myelin produced by oligodendrocytes (OLs). Oligodendrocyte precursor cells (OPCs) and mature OLs are CNS cell types essential for generating myelin sheath, which supports saltatory conduction and neuronal metabolic support. Although the roles of CNS resident cells (neurons, microglia, astrocytes) and peripheral immune cells in MS pathogenesis are well established, our understanding of how oligodendrocyte lineage cells (OLCs)—comprising OPCs and mature OLs—bidirectionally interact with these cell types to influence disease progression remains incomplete. Emerging evidence emphasizes the critical role of disease‐associated OLCs in neuroimmune responses and their underlying signaling mechanisms. Therefore, elucidating how pathological environments shaped by CNS and peripheral cells influence OLC function may identify critical therapeutic targets for promoting remyelination and recovery in MS. This review synthesizes current knowledge of OLC biology in health and disease, with emphasis on complex intercellular interactions that determine demyelination, remyelination, and axonal integrity in MS.

Decoding multiple sclerosis: linking autoimmunity, and nutrition/environmental factors to mitochondrial dysfunction and therapeutic opportunities

Characterization of myelin lipid changes across disease stages in experimental autoimmune encephalomyelitis 2302268

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The myelin sheath of the CNS is a highly specialized, lipid-rich membrane that acts as the primary target of autoimmunity in MS, leading to demyelination, axonal injury, and consequent neuronal dysfunction. While the immunopathogenesis of MS has been extensively studied, particularly autoreactive lymphocytes, cytokine networks, and myelin sheath targeted immune responses, the contribution of lipid metabolism to disease progression mechanisms remains relatively underexplored. Here, we investigated whether neuroinflammation promoted alterations in the myelin lipidome during the initial attack of disease and during disease relapses that could contribute to MS progression. We used mass spectrometry imaging (MSI), thiobarbituric acid reactant (TBARS) assays, and integrated immunohistochemistry to characterize lipid profiles, peroxidation, and spatial distribution in relapsing-remitting experimental autoimmune encephalomyelitis (EAE) models across disease stages. We identified significant lipid peroxidation during the acute phase of disease, with levels remaining elevated throughout remission, spatial heterogeneity of myelin sheath sulfatide distribution in the central nervous system, and disease-specific lipid modifications corresponding to inflammatory infiltrates, supporting the pathogenic role of oxidized lipids in MS. These findings provide novel insights into the dynamics of the CNS lipidome during neuroinflammation and suggest that myelin lipid alterations could contribute to MS progression through mechanisms independent of neuroinflammation. R21 NS137101-01 Neuroimmunology (NEUR)

Injury-transduced oligodendrocytes modulate neuroinflammation and glial activation in diseased and non-diseased central nervous system

Oligodendrocytes (OLs) are brain cells that make myelin, the insulating sheath that supports nerve signal transmission. Although oligodendrocyte dysfunction is common in the central nervous system (CNS), how these cells respond to injury remains incompletely understood. Here we show, using mouse models and mouse tissue analyses, that OLs respond to demyelinating diseases by increasing the expression and secretion of serine protease inhibitor clade A member 3N (SERPINA3N). This transition of homeostatic OLs to Serpina3n-expressing OLs (SerpinOLs) occurs not only in demyelinating disease, but also after stroke, endotoxin-induced injury, neurodegeneration, traumatic injury, and healthy aging. Mechanistically, direct injury to OLs, rather than inflammation alone, drives the transition. Phenotypically, SerpinOLs show inflammatory and immune-regulatory features and activation of signal transducer and activator of transcription 3 (STAT3), which is required for SERPINA3N induction. Functionally, SerpinOLs amplify neuroinflammation and glial activation toward pro-inflammatory and neurodegenerative states. Together, SerpinOLs represent a common population of injury-transduced OLs that contributes to CNS pathology beyond myelin production.

Selective GPR17 antagonism enhances structural and functional recovery in animal models of demyelination

Myelination, driven by differentiation of oligodendrocyte precursor cells, is critical for metabolic and structural support and efficient axonal signal transmission in neurons. Loss of myelin is a hallmark of multiple sclerosis and other devastating demyelinating disorders. As demyelination persists, neurons become increasingly vulnerable, leading to neurodegeneration and chronic disability. Restoring myelin through endogenous repair mechanisms offers a promising therapeutic approach to mitigate progressive neuronal loss. One key regulator of myelination is the G protein-coupled receptor 17, GPR17, whose chronic upregulation in oligodendrocyte precursor cells is commonly seen with myelin injury. In line with single-nucleus transcriptomic data showing predominant expression of GPR17 in committed oligodendrocyte precursor cells, our postmortem immunohistochemical analyses of MS patient tissue revealed a significant upregulation of GPR17+/BCAS1+ oligodendrocyte precursor cells adjacent to and in demyelinated lesions. Importantly, remyelinated lesions lacked GPR17 immunoreactivity, consistent with a model in which sustained GPR17 expression is associated with demyelination and impaired oligodendrocyte precursor cell differentiation. To test the impact of pharmacological GPR17 inhibition on remyelination, we evaluated the effects of a novel, selective GPR17 antagonist in cuprizone-induced murine demyelination models. This toxin-induced approach has been widely used to study mechanisms of de- and remyelination, in the absence of the full inflammatory complexity of demyelinating diseases such as multiple sclerosis. We show that oral treatment results in robust functional recovery consistent with remyelination, as evidenced by improved spatial memory and recovery of visual evoked potential latency delays. GPR17 antagonism also accelerated structural remyelination in the corpus callosum and optic nerve. Together, these findings support a role for pharmacological GPR17 antagonism in promoting remyelination and highlight this G protein-coupled receptor as a promising therapeutic target for demyelinating disorders.