Neurotoxicity in Huntington Disease

Abstract

Huntington disease (HD) is an autosomal dominant, progressive, and neurodegenerative disorder, caused by an abnormal CAG expansion in the huntingtin (HTT) gene (Chromosome 4). The CAG repeat expansion mutation leads to an extended polyglutamine tract in the huntingtin protein, which in turn leads to cascades of molecular and cellular pathogenesis. HD is one of the most common neurogenetic disorders and the most common of at least nine polyglutamine diseases and has devastating consequences for patients and their families. The typical age of onset is in mid-life (30s–40s), and symptoms include involuntary movements, cognitive/behavioral dysfunction, and psychiatric disorders. While symptomatic treatments exist, these do not prolong survival, and median survival is approximately 20 years. HD strikes at a productive period in work and family life and requires a high level of complex care. Consequently, the direct and indirect cost of HD has been informally estimated to be over 2 billion dollars per year, in the United States alone. As a monogenic disorder, the genetic etiology of HD is well established. However, our understanding of the pathogenesis of HD, at molecular, cellular, and systems levels, is still evolving. In particular, mutation in the HTT gene appears to confer neurotoxicity on multiple levels, ranging from epigenetic, RNA, and protein levels, to intracellular, intercellular, and end-organ levels. Each of these areas will be reviewed in turn. While acknowledging that abnormal neurodevelopment may contribute to HD pathogenesis, focus will be placed on potential molecular and cellular mechanisms mediating neurotoxicity and associated neurodegeneration and their therapeutic implications.