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

被引：59

作者：

Aron, Rebecca ^{[1
,2
,3
,11
]}

Pellegrini, Pasquale ^{[1
,2
]}

Green, Edward W. ^{[4
,5
]}

Maddison, Daniel C. ^{[4
]}

Opoku-Nsiah, Kwadwo ^{[6
]}

Wong, Jinny S. ^{[1
,2
]}

Daub, Aaron C. ^{[1
,2
]}

Giorgini, Flaviano ^{[4
]}

Finkbeiner, Steven ^{[1
,2
,3
,7
,8
,9
,10
]}

机构：

[1] Gladstone Inst, Ctr Syst & Therapeut, 1650 Owens St, San Francisco, CA 94158 USA

[2] Gladstone Inst, Taube Koret Ctr Neurodegenerat Dis, 1650 Owens St, San Francisco, CA 94158 USA

[3] Taube Koret Ctr Neurodegenerat Dis, San Francisco, CA 94158 USA

[4] Univ Leicester, Dept Genet & Genome Biol, Coll Life Sci, Adrian Bldg,Univ Rd, Leicester LE1 7RH, Leics, England

[5] DKFZ, D-69120 Heidelberg, Germany

[6] Univ Calif San Francisco, Dept Pharmaceut Chem, Grad Program Chem & Chem Biol, San Francisco, CA 94158 USA

[7] Univ Calif San Francisco, Grad Program Biomed Sci, San Francisco, CA 94158 USA

[8] Univ Calif San Francisco, Grad Program Neurosci, San Francisco, CA 94158 USA

[9] Univ Calif San Francisco, Grad Program Med Scientist Training Program, San Francisco, CA 94158 USA

[10] Univ Calif San Francisco, Dept Neurol & Physiol, San Francisco, CA 94158 USA

[11] Yuman Therapeut, Cambridge, MA 02139 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国生物技术与生命科学研究理事会;

关键词：

MUTANT HUNTINGTIN; ALPHA-SYNUCLEIN; POLYGLUTAMINE DISEASES; PROTEIN; TOXICITY; DEGRADATION; DROSOPHILA; NEURONS; EXPRESSION; MODIFIERS;

D O I：

10.1038/s41467-018-05653-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：14

共 56 条

[1]

Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].