Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.
Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease.
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去泛素酶USP12在亨廷顿氏病模型中诱导自噬和赋予神经保护作用。
DOI：
10.1038/s41467-018-05653-z
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发表时间：
2018-09-28
影响因子：
16.6
通讯作者：
Finkbeiner S
中科院分区：
文献类型：
--
作者：
Aron R;Pellegrini P;Green EW;Maddison DC;Opoku-Nsiah K;Oliveira AO;Wong JS;Daub AC;Giorgini F;Muchowski P;Finkbeiner S
亨廷顿病是由多聚谷氨酰胺扩增的突变亨廷顿蛋白（mHTT）引起的进行性神经退行性疾病。在这里，我们发现去泛素化酶Usp 12在亨廷顿病啮齿动物和患者源性人类神经元以及果蝇中挽救了mHT介导的神经变性。Usp 12的神经保护作用可能是相关的去泛素化酶中特异性的，因为密切相关的同源物Usp 46不抑制mHTT介导的毒性。从机制上讲，我们将Usp12确定为神经元自噬的有效诱导剂。Usp12过表达加速自噬通量，并诱导自噬结构增加约6倍，通过超微结构分析确定，而内源性Usp12的抑制减慢自噬。令人惊讶的是，Usp12的催化活性并不是防止神经变性或诱导自噬所必需的。这些发现确定了去泛素化酶Usp12作为神经元蛋白质稳态和mHTT介导的神经变性的调节剂。在退化的神经元中经常发现毒性蛋白质的异常积聚。在这里，Aron及其同事表明，去泛素化酶Usp 12的非酶功能可以通过诱导神经元自噬功能减轻突变亨廷顿蛋白引起的神经元细胞死亡。
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.
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影响因子：
4.8
作者：
Cohn, Martin A.;Kee, Younghoon;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
DOI：
10.1073/pnas.1402215111
发表时间：
2014-04-15
影响因子：
11.1
作者：
Bhat, Kavita P.;Yan, Sen;Li, Xiao-Jiang
通讯作者：
Li, Xiao-Jiang
影响因子：
3.3
作者：
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通讯作者：
Canals, Josep M.
影响因子：
4.8
作者：
Joo, Heui-Yun;Jones, Amada;Wang, Hengbin
通讯作者：
Wang, Hengbin