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

From Yeast to Therapeutic? Yeast has shown some promise as a model system to generate lead compounds that could have therapeutic potential for the cellular problems associated with neurodegenerative diseases. Along these lines, Tardiff et al. (p. 979, published online 24 October) and Chung et al. (p. 983, published online 24 October) describe the results of multiple screens in yeast that lead to the identification of a potential therapeutic compound to combat the cytotoxic affect of α-synuclein accumulation. The compound was able to reverse the pathological hallmarks of Parkinson's disease in cultured neurons derived from patients with α-synuclein–induced Parkinson's disease dementia. Screening in yeast yields an effective therapeutic for Parkinson’s patient–derived neuronal stem cells. 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.