Huntington's disease

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder that primarily targets medium spiny neurons, leading to the gradual atrophy of the striatum. The disease affects 4.1-8.4 cases per 100,000 persons in the USA and Europe and typically displays relentless progression of cognitive and motor deficits over a period of 15-20 years. Its most striking clinical feature is the chorea: involuntary complex body movements involving the entire musculature with stereotyped patterns. HD is an autosomal dominant disorder caused by the expansion of an uninterrupted track of CAG repeats within exon 1 of the gene huntingtin (Htt). Htt codes for a soluble and multi-domain protein; the N-terminal fragment interacts with a wide variety of protein partners. Further, Htt contains several consensus sites for posttranslational modifications with significant functional roles, including protease cleavage, SUMOylation, ubiquitination, phosphorylation, palmitoylation, and acetylation. Notably, Htt displays functional pleiotropism, including prominent roles in gene transcription, endocytosis, intracellular trafficking, synaptic spine morphogenesis, apoptosis, and neural development. The abnormal trinucleotide expansion in the Htt gene product triggers a complex combination of gain- and loss-of-function pathological mechanisms that synergistically contribute to disease pathogenesis. Thus, HD pathogenesis may involve the interplay of multiple pathological cascades, including transcriptional dysregulation, neuronal excitotoxicity, impairments in the expression and delivery of neurotrophic factors, mitochondrial dysfunction, aberrant activation of proteases, and protein turnover, including aggregation. Indeed, it is likely that different pathological processes mediating progressive cellular dysfunction and late-onset cell death are operating in discrete brain regions in HD. The enormous strides that have been made in the understanding of the molecular pathogenesis of HD as well as in establishing emerging links between impairments in neural development and neuronal dysfunction have furnished the conceptual underpinnings and the novel molecular targets for devising innovative therapeutic strategies to prevent disease onset and to halt disease progression.