Identification and Rescue of α-Synuclein Toxicity in Parkinson Patient-Derived Neurons

被引：367

作者：

Chung, Chee Yeun ^{[1
]}

Khurana, Vikram ^{[1
,2
,3
]}

Auluck, Pavan K. ^{[1
,3
,4
]}

Tardiff, Daniel F. ^{[1
]}

Mazzulli, Joseph R. ^{[2
,3
]}

Soldner, Frank ^{[1
]}

Baru, Valeriya ^{[1
,5
]}

Lou, Yali ^{[1
,5
]}

Freyzon, Yelena ^{[1
]}

Cho, Sukhee ^{[6
]}

Mungenast, Alison E. ^{[6
]}

Muffat, Julien ^{[1
]}

Mitalipova, Maisam ^{[1
]}

Pluth, Michael D. ^{[7
]}

Jui, Nathan T. ^{[7
]}

Schuele, Birgitt ^{[8
]}

Lippard, Stephen J. ^{[7
]}

Tsai, Li-Huei ^{[5
,6
]}

Krainc, Dimitri ^{[2
,3
]}

Buchwald, Stephen L. ^{[7
]}

Jaenisch, Rudolf ^{[1
,9
]}

Lindquist, Susan ^{[1
,5
,9
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA

[5] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[6] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA

[7] MIT, Dept Chem, Cambridge, MA 02139 USA

[8] Parkinsons Inst, Sunnyvale, CA 94085 USA

[9] MIT, Dept Biol, Cambridge, MA 02139 USA

来源：

SCIENCE | 2013年 / 342卷 / 6161期

基金：

美国国家科学基金会;

关键词：

NEURODEGENERATION; NITRATION; NETWORK; STRESS; RISK;

D O I：

10.1126/science.1245296

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：

07 ; 0710 ; 09 ;

摘要：

The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein (alpha syn), a key protein involved in Parkinson's disease (PD). We generated cortical neurons from iPS cells of patients harboring alpha syn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha syn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.

引用

页码：983 / 987

页数：5

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