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

Nat Commun. 2018 Sep 28;9(1):3191. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Cells, Cultured
  • Drosophila melanogaster
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Mutation
  • Neurons / cytology
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Neuroprotection / genetics*
  • RNA Interference
  • Rats
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism


  • HTT protein, human
  • Huntingtin Protein
  • USP12 protein, human
  • Ubiquitin Thiolesterase