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Compounds from an unbiased chemical screen reverse both ER-to-Golgi trafficking defects and mitochondrial dysfunction in Parkinson's disease models


alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function is poorly characterized. It is of great interest to human biology and medicine because alpha-syn dysfunction is associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created a yeast model of alpha-syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to alpha-syn expression. We also uncovered a core group of proteins with diverse activities related to alpha-syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of alpha-syn also exhibits strong defects in mitochondrial function. Unlike our previous strain, genetic suppression of endoplasmic reticulum (ER)-to-Golgi trafficking alone does not suppress alpha-syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of alpha-syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced alpha-syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of alpha-syn foci, re-established ER-to-Golgi trafficking and ameliorated alpha-syn-mediated damage to mitochondria. They also corrected the toxicity of alpha-syn in nematode neurons and in primary rat neuronal midbrain cultures. Remarkably, the compounds also protected neurons against rotenone-induced toxicity, which has been used to model the mitochondrial defects associated with PD in humans. That single compounds are capable of rescuing the diverse toxicities of alpha-syn in yeast and neurons suggests that they are acting on deeply rooted biological processes that connect these toxicities and have been conserved for a billion years of eukaryotic evolution. Thus, it seems possible to develop novel therapeutic strategies to simultaneously target the multiple pathological features of PD.

Type Journal
ISBN 1754-8411 (Electronic) 1754-8403 (Linking)
Authors Su, L. J.; Auluck, P. K.; Outeiro, T. F.; Yeger-Lotem, E.; Kritzer, J. A.; Tardiff, D. F.; Strathearn, K. E.; Liu, F.; Cao, S.; Hamamichi, S.; Hill, K. J.; Caldwell, K. A.; Bell, G. W.; Fraenkel, E.; Cooper, A. A.; Caldwell, G. A.; McCaffery, J. M.; Rochet, J. C.; Lindquist, S.;
Publisher Name Disease Models & Mechanisms
Published Date 2010-01-01 00:00:00
Published Volume 3
Published Issue 3-4
Published Pages 194-208
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version