학술논문
Identification and rescue of [alpha]-synuclein toxicity in Parkinson patient-derived neurons
REPORTS
REPORTS
Document Type
Report
Author abstract
Author abstract
Author
Chung, Chee Yeun; Khurana, Vikram; Auluck, Pavan K.; Tardiff, Daniel F.; Mazzulli, Joseph R.; Soldner, Frank; Baru, Valeriya; Lou, Yali; Freyzon, Yelena; Cho, Sukhee; Mungenast, Alison E.; Muffat, Julien; Mitalipova, Maisam; Pluth, Michael D.; Jui, Nathan T.; Schule, Birgitt; Lippard, Stephen J.; Tsai, Li-Huei; Krainc, Dimitri; Buchwald, Stephen L.; Jaenisch, Rudolf; Lindquist, Susan
Source
Science. Nov 22, 2013, Vol. 342 Issue 6161, p983, 5 p.
Subject
Language
English
ISSN
0036-8075
Abstract
The induced pluripotent stern (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 pathotogic phenotypes in these neurons. 10.1126/science.1245296