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Science. 2013 Nov 22;342(6161):983-7. doi: 10.1126/science.1245296. Epub 2013 Oct 24.

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

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

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

PMID:
24158904
PMCID:
PMC4022187
DOI:
10.1126/science.1245296
[Indexed for MEDLINE]
Free PMC Article

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