Review Article | Published:

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Acta Pharmacologica Sinica volume 39, pages 754769 (2018) | Download Citation

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Abstract

Many neurodegenerative diseases are characterized by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular, the ubiquitin-proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides new insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

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Acknowledgements

The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute[OGI-055], Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant No 115766], Janssen, Merck KGaA, MSD, Novartis Pharma AG, Ontario Ministry of Research, Innovation and Sciences (MRIS), Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust. This work is also supported by additional funding awarded to Y.T. (Discovery Grant: RGPIN-2017-06520) from the Natural Sciences and Engineering Research Council of Canada.

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  1. Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, Ontario M5G 1L7, Canada

    • Rachel J Harding
    •  & Yu-feng Tong
  2. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5G 1L7, Canada

    • Yu-feng Tong

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Correspondence to Yu-feng Tong.

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https://doi.org/10.1038/aps.2018.11

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