Molecular and Cellular Insights into Huntington’s Disease Pathophysiology

Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder characterized by progressive motor dysfunction, cognitive deterioration, and psychiatric symptoms. It primarily affects the basal ganglia, especially the striatum, resulting in both structural and functional abnormalities. At the molecular level, the disease is driven by a toxic gain-of-function mutation in the huntingtin gene, leading to intracellular dysfunctions including protein misfolding, impaired axonal transport, transcriptional dysregulation, mitochondrial failure, oxidative stress, and excitotoxicity. This review provides a comprehensive overview of HD pathophysiology, emphasizing the mechanisms underlying striatal vulnerability and basal ganglia circuit disruption. Particular attention is given to mitochondrial dysfunction, oxidative damage, neuroinflammation, and the role of the renin-angiotensin system (RAS), including the emerging neuroprotective potential of the ACE2/Ang-(1–7)/Mas receptor axis. Insights into these interconnected pathways not only deepen our understanding of disease progression but also highlight novel therapeutic targets. Despite substantial advances in elucidating HD pathology, a cure remains elusive, reinforcing the urgency of exploring targeted interventions that may mitigate neurodegeneration and enhance patient outcomes