Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons

Chee Yeun Chung, Vikram Khurana, Pavan K. Auluck, Daniel F. Tardiff, Joseph R. Mazzulli, Frank Soldner, Valeriya Baru, Yali Lou, Yelena Freyzon, Sukhee Cho, Alison E. Mungenast, Julien Muffat, Maisam Mitalipova, Michael D. Pluth, Nathan T. Jui, Birgitt Schul̈e, Stephen J. Lippard, Li Huei Tsai, Dimitri Krainc, Stephen L. BuchwaldRudolf Jaenisch, Susan Lindquist

Research output: Contribution to journalArticle

263 Scopus citations

Abstract

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 a-synuclein (asyn), a key protein involved in Parkinson 's disease (PD). We generated cortical neurons from iPS cells of patients harboring asyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of asyn 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.

Original languageEnglish (US)
Pages (from-to)983-987
Number of pages5
JournalScience
Volume342
Issue number6161
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

ASJC Scopus subject areas

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    Chung, C. Y., Khurana, V., Auluck, P. K., Tardiff, D. F., Mazzulli, J. R., Soldner, F., Baru, V., Lou, Y., Freyzon, Y., Cho, S., Mungenast, A. E., Muffat, J., Mitalipova, M., Pluth, M. D., Jui, N. T., Schul̈e, B., Lippard, S. J., Tsai, L. H., Krainc, D., ... Lindquist, S. (2013). Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science, 342(6161), 983-987. https://doi.org/10.1126/science.1245296