Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion mutation in the huntingtin protein. Expansions above 40 polyglutamine repeats are invariably fatal, following a symptomatic period characterised by choreiform movements, behavioural abnormalities, and cognitive decline. While mutant huntingtin (mHtt) is widely expressed from early life, most patients with HD present in mid-adulthood, highlighting the role of ageing in disease pathogenesis. mHtt undergoes proteolytic cleavage, misfolding, accumulation, and aggregation into inclusion bodies. The emerging model of HD pathogenesis proposes that the chronic production of misfolded mHtt overwhelms the chaperone machinery, diverting other misfolded clients to the proteasome and the autophagy pathways, ultimately leading to a global collapse of the proteostasis network. Multiple converging hypotheses also implicate ageing and its impact in the dysfunction of organelles as additional contributing factors to the collapse of proteostasis in HD. In particular, mitochondrial function is required to sustain the activity of ATP-dependent chaperones and proteolytic machinery. Recent studies elucidating mitochondria-endoplasmic reticulum interactions and uncovering a dedicated proteostasis machinery in mitochondria, suggest that mitochondria play a more active role in the maintenance of cellular proteostasis than previously thought. The enhancement of cytosolic proteostasis pathways shows promise for HD treatment, protecting cells from the detrimental effects of mHtt accumulation. In this review, we consider how mHtt and its post translational modifications interfere with protein quality control pathways, and how the pharmacological and genetic modulation of components of the proteostasis network impact disease phenotypes in cellular and in vivo HD models.
Highlights
Huntington’s Disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion mutation in the exon 1 of the huntingtin (Htt) gene
We consider the interplay between diffuse and aggregated Mutant Htt (mHtt), the stress imposed by such mHtt species on molecular chaperones and proteolytic pathways, and how this might synergise with ageing-associated changes in the proteostasis network
The current model to account for the impairment of proteostasis by mHtt proposes a gradual, yet global collapse of the proteostasis network that synergises with ageing-associated changes in proteostasis capacity
Summary
Huntington’s Disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion mutation in the exon 1 of the huntingtin (Htt) gene. MHtt is expressed throughout the life of the individual, HD onset typically occurs around the 4th decade of life This suggests that there are compensatory mechanisms that limit mHtt proteotoxicity early in life, but that such mechanisms are eventually overtaken by ageing and disease progression (Arrasate and Finkbeiner, 2012). The proteostasis network can be induced in response to protein misfolding and aggregation, and comprises several quality control systems, such as molecular chaperones and proteolytic pathways (Hipp et al, 2014). When misfolded proteins escape chaperone control they are usually targeted for degradation, either through the ubiquitin-proteasome system (UPS) or by autophagy (Hipp et al, 2014). We consider the interplay between diffuse and aggregated mHtt, the stress imposed by such mHtt species on molecular chaperones and proteolytic pathways, and how this might synergise with ageing-associated changes in the proteostasis network. We conclude with a discussion of the current model of impaired proteostasis in HD, how it might relate to selective neurodegeneration, and the implications for future directions of research in this field
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