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000141978 1001_ $$aAron, Rebecca$$b0
000141978 245__ $$aDeubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.
000141978 260__ $$a[London]$$bNature Publishing Group UK$$c2018
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000141978 520__ $$aHuntington's disease is a progressive neurodegenerative disorder caused by polyglutamine-expanded mutant huntingtin (mHTT). Here, we show that the deubiquitinase Usp12 rescues mHTT-mediated neurodegeneration in Huntington's disease rodent and patient-derived human neurons, and in Drosophila. The neuroprotective role of Usp12 may be specific amongst related deubiquitinases, as the closely related homolog Usp46 does not suppress mHTT-mediated toxicity. Mechanistically, we identify Usp12 as a potent inducer of neuronal autophagy. Usp12 overexpression accelerates autophagic flux and induces an approximately sixfold increase in autophagic structures as determined by ultrastructural analyses, while suppression of endogenous Usp12 slows autophagy. Surprisingly, the catalytic activity of Usp12 is not required to protect against neurodegeneration or induce autophagy. These findings identify the deubiquitinase Usp12 as a regulator of neuronal proteostasis and mHTT-mediated neurodegeneration.
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000141978 7001_ $$aPellegrini, Pasquale$$b1
000141978 7001_ $$0P:(DE-He78)9b97ca569bcb00dfda69382bc7261700$$aGreen, Edward$$b2$$udkfz
000141978 7001_ $$aMaddison, Daniel C$$b3
000141978 7001_ $$aOpoku-Nsiah, Kwadwo$$b4
000141978 7001_ $$aWong, Jinny S$$b5
000141978 7001_ $$aDaub, Aaron C$$b6
000141978 7001_ $$aGiorgini, Flaviano$$b7
000141978 7001_ $$aFinkbeiner, Steven$$b8
000141978 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-018-05653-z$$gVol. 9, no. 1, p. 3191$$n1$$p3191$$tNature Communications$$v9$$x2041-1723$$y2018
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