Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Science (American Association for the Advancement of Science), 2013-11, Vol.342 (6161), p.983-987

Ort / Verlag

Washington, DC: American Association for the Advancement of Science

Erscheinungsjahr

2013

Link zum Volltext

Quelle

American Association for the Advancement of Science

Beschreibungen/Notizen

• 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 α-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.