Journal
SCIENCE
Volume 342, Issue 6161, Pages 983-987Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1245296
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Funding
- Howard Hughes Medical Institute
- JPB Foundation
- NIH/National Institute on Aging [K01 AG038546]
- American Brain Foundation
- Parkinson's Disease Foundation
- NIH [5 R01CA084198]
- NSF
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0907905] Funding Source: National Science Foundation
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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.
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