Center for Systems and Therapeutics & Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, 1650 Owens St., San Francisco, CA, 94158, USA.
Taube-Koret Center for Neurodegenerative Disease, San Francisco, CA, 94158, USA.
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.
亨廷顿病是一种由多聚谷氨酰胺扩展突变亨廷顿蛋白（mHTT）引起的进行性神经退行性疾病。在这里，我们表明去泛素化酶 Usp12 可挽救亨廷顿病啮齿动物和患者来源的人神经元以及果蝇中的 mHTT 介导的神经退行性变。Usp12 的神经保护作用可能在相关去泛素化酶中是特异性的，因为密切相关的同源物 Usp46 不能抑制 mHTT 介导的毒性。在机制上，我们确定 Usp12 是神经元自噬的有效诱导剂。Usp12 的过表达加速了自噬流，并通过超微结构分析确定自噬结构增加了约六倍，而内源性 Usp12 的抑制则减缓了自噬。令人惊讶的是，Usp12 的催化活性对于防止神经退行性变或诱导自噬并非必需。这些发现确定去泛素化酶 Usp12 是神经元蛋白质稳态和 mHTT 介导的神经退行性变的调节剂。
