Oligodendrocyte pathology in Huntington's disease: from mechanisms to therapeutics.

Myelin, the lipid-rich structure formed by oligodendrocytes (OLGs) in the central nervous system, is fundamental for normal motor, sensory, and cognitive functions. Myelin pathology in Huntington's disease (HD) appears early in the course of the disease and is progressive in nature, pointing to its possible contribution to neurological manifestations of the disease. Increasing evidence suggests that cell-intrinsic deficits in OLGs are the earliest cause of myelination abnormalities in HD, with several OLG-specific pathogenic mechanisms involved, including altered lipid metabolism, modifications in epigenetic signaling, and dysregulated activity of transcription factors. Understanding the mechanisms that underlie myelination deficits in HD can expand therapeutic options to include targeting oligodendroglial pathology as an additional treatment avenue. Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of the role of OLGs in the pathogenesis of neurodegenerative diseases (NDDs), including Huntington's disease (HD), a prototypic NDD caused by a polyglutamine tract expansion in huntingtin (HTT), which results in gain- and loss-of-function effects. Clinically, HD is characterized by a constellation of motor, cognitive, and psychiatric disturbances. White matter (WM) structures, representing myelin-rich regions of the brain, are profoundly affected in HD, and recent findings reveal oligodendroglia dysfunction as an early pathological event. Here, we focus on mechanisms that underlie oligodendroglial deficits and dysmyelination in the progression of the disease, highlighting the pathogenic contributions of mutant HTT (mHTT). We also discuss potential therapeutic implications involving these molecular pathways. Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of the role of OLGs in the pathogenesis of neurodegenerative diseases (NDDs), including Huntington's disease (HD), a prototypic NDD caused by a polyglutamine tract expansion in huntingtin (HTT), which results in gain- and loss-of-function effects. Clinically, HD is characterized by a constellation of motor, cognitive, and psychiatric disturbances. White matter structures, representing myelin-rich regions of the brain, are profoundly affected in HD, and recent findings reveal oligodendroglia dysfunction as an early pathological event. Here, we focus on mechanisms that underlie oligodendroglial deficits and dysmyelination in the progression of the disease, highlighting the pathogenic contributions of mutant HTT. We also discuss potential therapeutic implications involving these molecular pathways. [ABSTRACT FROM AUTHOR]