Molecular mechanisms, clinical phenotypes, and advances in Huntington’s disease therapeutics

Huntington’s disease (HD) is a progressive, inherited neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat number in the Huntingtin gene. Clinically, HD manifests as involuntary choreatic movements, cognitive decline, behavioral, and psychiatric disturbances. At the pathological level, HD is characterized by the accumulation of mutant Huntingtin protein as intranuclear inclusions and progressive neuronal loss, primarily in the striatum and cerebral cortex. Over the decades, remarkable scientific advancements have deepened our understanding of the major pathological events, the clinical characteristics, and the potential role of peripheral organs and tissues in the disease. These insights have paved the way for the identification of more promising biomarkers and potential therapeutic targets. This review integrates the molecular and pathological understanding of HD with recent mechanistic and translational advances. This review has also sought to shed light on future directions for investigating disease pathology and advancing novel therapeutics. Although substantial progress has been made, the incurable nature of HD underscores the need for continued research, as discussed towards the end of this review. Graphical Abstract