Identification and Rescue of α-Synuclein Toxicity in Parkinson Patient–Derived Neurons
Year: 2013
Type: article
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.
Source: Science
Authors: 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 Schüle, Stephen J. Lippard, Li-Huei Tsai, Dimitri Krainc, Stephen L. Buchwald, Rudolf Jaenisch, Susan Lindquist
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1737649554, Molecular Dissection of Synucleinopathies Using Yeast, Rodent and Human iPS Cells, Programming and Reprogramming Human Cells, G5392660228, Late Transition Metal Catalysts for Organic Synthesis, Massachusetts Alzheimer's Disease Research Center, The Role of Lysosomal Glucocerebrosidase in Synucleinopathies, Massachusetts Alzheimer's Disease Research Center (MADRC)
OpenAlex ID: W2143515674