Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.
journal contributionposted on 2019-07-25, 13:46 authored by R Aron, P Pellegrini, EW Green, DC Maddison, K Opoku-Nsiah, JS Wong, AC Daub, F Giorgini, S Finkbeiner
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.
We thank members of the Finkbeiner Laboratory for helpful suggestions and comments; Gary Howard and Eric Martens for editorial assistance; and Kelley Nelson for administrative assistance. We thank Larry Marsh and Leslie Thompson for providing the w;+;UAS Htt93Q exon 1 Drosophila melanogaster strain. This work was done with support from NIH NS039074, U54 HG008105, and NS R37101996; the Taube/Koret Center; and the Gladstone Institutes (S.F.). E.W.G. was supported by a research contract from the CHDI Foundation awarded to F.G., while D.C.M. was supported by a Ph.D. studentship from the Midlands Integrative Biosciences Training Partnership funded by the BBSRC. We thank the Hereditary Disease Foundation for fellowship support to R.A.
CitationNature Communications, 2018, 9, Article number: 3191
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology
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