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

Rebecca Aron, Pasquale Pellegrini, Edward W. Green, Daniel C. Maddison, Kwadwo Opoku-Nsiah, Ana Osório Oliveira, Jinny S. Wong, Aaron C. Daub, Flaviano Giorgini, Paul Muchowski and Steven Finkbeiner ()
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Rebecca Aron: Gladstone Institutes
Pasquale Pellegrini: Gladstone Institutes
Edward W. Green: University of Leicester
Daniel C. Maddison: University of Leicester
Kwadwo Opoku-Nsiah: University of California—San Francisco
Ana Osório Oliveira: Gladstone Institutes
Jinny S. Wong: Gladstone Institutes
Aaron C. Daub: Gladstone Institutes
Flaviano Giorgini: University of Leicester
Paul Muchowski: Gladstone Institutes
Steven Finkbeiner: Gladstone Institutes

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05653-z

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