ハンチントン病の発生病態を解明するためのマウスモデル

Huntington's disease (HD) has traditionally been viewed as a late-onset neurodegenerative disorder. However, emerging evidence suggests that differences in the stoichiometry of wild-type huntingtin (HTT) and mutant huntingtin (mHTT) exert a complex spectrum of pathogenic effects during early brain development, preceding the onset of overt clinical signs by several decades. In this review, we examine how various HD mouse models have revealed distinct yet frequently converging developmental abnormalities through the dynamic interplay of novel early pathogenic and homeostatic processes. Full-length transgenic models like BACHD demonstrate early glial dysmaturation, corticostriatal synaptic deficits, and behavioral phenotypes emerging during infancy. Truncated fragment models such as R6/2 exhibit aggressive phenotypes resembling juvenile HD, with early neuronal and myelination defects. Knock-in models, including HdhQ111, HdhQ140, and zQ175, highlight CAG-length-dependent disruptions in neural progenitor cell dynamics, synaptic formation, and cortical plasticity. Loss-of-function models further implicate wild-type HTT in neural patterning and germ layer specification, recapitulating HD-like features in the absence of mHTT overexpression. Together, these models underscore a developmental dimension to HD pathogenesis and suggest that early-life circuit miswiring, glial dysfunction, and impaired integrity of the specification, maturation, and maintenance of neural cell identity and functions may prime the brain for later neurodegeneration. Understanding these early disruptions is essential for identifying novel early therapeutic windows, biomarkers, and molecular targets essential for devising true disease-modifying paradigms aimed at delaying, reversing, or even preventing the onset of disease hallmarks.