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

• Published in: Nature communications Vol. 9; no. 1; pp. 3191 - 14
• Main Authors: Aron, Rebecca, Pellegrini, Pasquale, Green, Edward W., Maddison, Daniel C., Opoku-Nsiah, Kwadwo, Oliveira, Ana Osório, Wong, Jinny S., Daub, Aaron C., Giorgini, Flaviano, Muchowski, Paul, Finkbeiner, Steven
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.09.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 13/109; 13/51; 13/89; 14; 14/28; 14/35; 14/56; 14/63; 631/378/1689/1558; 631/45/173; 64/24; 64/86; Animal models; Animals; Autophagy; Autophagy - genetics; Catalysis; Catalytic activity; Cell death; Cells, Cultured; Drosophila melanogaster; Fruit flies; Gene Expression Regulation; HEK293 Cells; Homology; Humanities and Social Sciences; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington Disease - metabolism; Huntingtons disease; multidisciplinary; Mutants; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - cytology; Neurons - metabolism; Neurons - ultrastructure; Neuroprotection; Neuroprotection - genetics; Phagocytosis; Polyglutamine; Rats; RNA Interference; Science; Toxicity; Trinucleotide repeat diseases; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05653-z

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. Abnormal accumulations of toxic proteins are often found in degenerating neurons. Here, Aron and colleagues show that non-enzymatic function of deubiquitinase Usp12 can mitigate neuronal cell death caused by mutant Huntingtin by inducing neuronal autophagic function.