Yeast Reveal a ‘Druggable’ Rsp5/Nedd4 Network That Ameliorates α-Synuclein Toxicity in Neurons
Author(s)Jui, Nathan T.; Buchwald, Stephen Leffler; Lindquist, Susan; Tardiff, Daniel F.; Khurana, Vikram; Tambe, Mitali A.; Thompson, Michelle L.; Chung, Chee Yeun; Kamadurai, Hari B.; Kim, Hyoung Tae; Lancaster, Alex K.; Caldwell, Kim A.; Caldwell, Guy A.; Rochet, Jean-Christophe; ... Show more Show less
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α-Synuclein (α-syn) is a small lipid-binding protein implicated in several neurodegenerative diseases, including Parkinson’s disease, whose pathobiology is conserved from yeast to man. There are no therapies targeting these underlying cellular pathologies, or indeed those of any major neurodegenerative disease. Using unbiased phenotypic screens as an alternative to target-based approaches, we discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from α-syn toxicity. Three chemical genetic screens in wild-type yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5/Nedd4. These same steps were perturbed by α-syn itself. Thus, NAB identifies a druggable node in the biology of α-syn that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum–to-Golgi vesicle trafficking.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemistry; Whitehead Institute for Biomedical Research
American Association for the Advancement of Science (AAAS)
Tardiff, Daniel F., Nathan T. Jui, Vikram Khurana, Mitali A. Tambe, Michelle L. Thompson, Chee Yeun Chung, Hari B. Kamadurai, et al. “Yeast Reveal a ‘Druggable’ Rsp5/Nedd4 Network That Ameliorates α-Synuclein Toxicity in Neurons.” Science 342, no. 6161 (October 24, 2013): 979–983.
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