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Despite its monogenic etiology, the pathogenic mechanisms of Huntington's disease (HD) have been challenging to disentangle. Mouse models of HD recapitulate several disease features, including striatum-selective, mutant Huntingtin (mHTT) CAG-repeat length–dependent and age-dependent disease processes, offering tools to study HD pathogenesis in vivo. Systems biology integrates large-scale molecular profiling approaches with unbiased bioinformatic tools (e.g., coexpression network analysis) to provide high-dimensional, information-rich, and reproducible findings that can inform disease mechanisms. Recent transcriptomic, epigenomic, and proteomic studies have uncovered key roles for expanded and uninterrupted mHTT CAG-repeats and other molecular factors in striatum-selective pathogenesis including transcriptional dysregulation in HD. Cell-type-specific or single-cell profiling reveals distinct …