Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.

Aron, Rebecca, Pellegrini, Pasquale, Green, Edward W., Maddison, Daniel C. ORCID: https://orcid.org/0000-0003-3038-1687, Opoku-Nsiah, Kwadwo, Oliveira, Ana Osório, Wong, Jinny S., Daub, Aaron C., Giorgini, Flaviano, Muchowski, Paul and Finkbeiner, Steven 2018. Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease. Nature Communications 9 (1) , 3191. 10.1038/s41467-018-05653-z

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Abstract

Huntington’s disease is a progressive neurodegenerative disorder caused by polyglutamine-expanded mutant huntingtin (mHTT). Here, we show that the deubiquitinase Usp12 rescues mHTT-mediated neurodegeneration in Huntington’s disease rodent and patient-derived human neurons, and in Drosophila. The neuroprotective role of Usp12 may be specific amongst related deubiquitinases, as the closely related homolog Usp46 does not suppress mHTT-mediated toxicity. Mechanistically, we identify Usp12 as a potent inducer of neuronal autophagy. Usp12 overexpression accelerates autophagic flux and induces an approximately sixfold increase in autophagic structures as determined by ultrastructural analyses, while suppression of endogenous Usp12 slows autophagy. Surprisingly, the catalytic activity of Usp12 is not required to protect against neurodegeneration or induce autophagy. These findings identify the deubiquitinase Usp12 as a regulator of neuronal proteostasis and mHTT-mediated neurodegeneration.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	4 August 2022
Date of Acceptance:	12 July 2018
Last Modified:	06 Jan 2024 04:40
URI:	https://orca.cardiff.ac.uk/id/eprint/151326

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