L. J Su, P. K Auluck, T. F Outeiro, E Yeger Lotem, J. A Kritzer, D. F Tardiff, K. E Strathearn, F Liu, S Cao, S Hamamichi, K. J Hill, K. A Caldwell, G. W Bell, E Fraenkel, A. A Cooper, G. A Caldwell, J. M McCaffery, J. C Rochet and S. Lindquist
Disease Models and Mechanisms, 2010, 3(3-4), 194-208. DOI: 10.1242/dmm.004267
Linhui Julie Su, Pavan K. Auluck, Tiago Fleming Outeiro, Esti Yeger-Lotem, Joshua A. Kritzer, Daniel F. Tardiff, Katherine E. Strathearn, Fang Liu, Songsong Cao, Shusei Hamamichi, Kathryn J. Hill, Kim A. Caldwell, George W. Bell, Ernest Fraenkel, Antony A. Cooper, Guy A. Caldwell, J. Michael McCaffery, Jean-Christophe Rochet, and Susan Lindquist
-Synuclein (-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 -syn dysfunction is associated with several neurodegenerative disorders, including Parkinson’s disease (PD). We previously created a yeast model of -syn pathobiology, which established vesicle trafficking as a process that is particularly sensitive to -syn expression. We also uncovered a core group of proteins with diverse activities related to -syn toxicity that is conserved from yeast to mammalian neurons. Here, we report that a yeast strain expressing a somewhat higher level of -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 -syn toxicity in this strain. In an effort to identify individual compounds that could simultaneously rescue these apparently disparate pathological effects of -syn, we screened a library of 115,000 compounds. We identified a class of small molecules that reduced -syn toxicity at micromolar concentrations in this higher toxicity strain. These compounds reduced the formation of -syn foci, re-established ER-to-Golgi trafficking and ameliorated -syn-mediated damage to mitochondria. They also corrected the toxicity of -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 -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.