Huntington's disease: underlying molecular mechanisms and emerging concepts

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder for which no disease modifying treatments exist. Many molecular changes and cellular consequences that underlie HD are observed in other neurological disorders, suggesting that common pathological mechanisms and pathways may exist. Recent findings have enhanced our understanding of the way cells regulate and respond to expanded polyglutamine proteins such as mutant huntingtin. These studies demonstrate that in addition to effects on folding, aggregation, and clearance pathways, a general transcriptional mechanism also dictates the expression of polyglutamine proteins. Here, we summarize the key pathways and networks that are important in HD in the context of recent therapeutic advances and highlight how their interplay may be of relevance to other protein folding disorders.

Keywords: Huntington's disease; molecular mechanisms; therapeutic approaches.

Figure 1. Major cellular pathways disrupted in Huntington’s disease

A diverse array of cellular processes is disturbed by the presence of mHTT. Here we depict a neuron and demonstrate the major sites of molecular disruption caused by the presence of mHTT. Roman numerals indicate which zoomed-in views (surrounding boxes) correspond to particular areas/processes in the cell. We provide a simplified over-view of the pathogenic pathways in HD discussed in our review, specifically, (i) transcriptional dysregulation of basal and inducible gene expression, (ii) impaired protein degradation, (iii) altered protein folding, (iv) disrupted synaptic signalling, and (v) perturbed energy metabolism through altered mitochondrial maintenance and localization. Pathway dysfunction can arise from direct or indirect interference of key components by soluble, oligomeric and/or aggregated mHTT. While we represent each pathway as an insular process, in reality, disruptions in one pathway likely influence HD pathogenesis (at least in part) by exacerbating dysfunction of other key events.