defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of parkinsons disease缺陷在极长链脂肪酸合成增强α-突触核蛋白在酵母毒性的帕金森病模型.pdfVIP

Defects in Very Long Chain Fatty Acid Synthesis Enhance Alpha-Synuclein Toxicity in a Yeast Model of Parkinson’s Disease 1 1 2 2 1 Yong Joo Lee , Shaoxiao Wang , Sunny R. Slone , Talene A. Yacoubian , Stephan N. Witt * 1 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, Louisiana, United States of America, 2 Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Abstract We identified three S. cerevisiae lipid elongase null mutants (elo1D, elo2D, and elo3D) that enhance the toxicity of alpha- synuclein (a-syn). These elongases function in the endoplasmic reticulum (ER) to catalyze the elongation of medium chain fatty acids to very long chain fatty acids, which is a component of sphingolipids. Without a-syn expression, the various elo mutants showed no growth defects, no reactive oxygen species (ROS) accumulation, and a modest decrease in survival of aged cells compared to wild-type cells. With (WT, A53T or E46K) a-syn expression, the various elo mutants exhibited severe growth defects (although A30P had a negligible effect on growth), ROS accumulation, aberrant protein trafficking, and a dramatic decrease in survival of aged cells compared to wild-type cells. Inhibitors of ceramide synthesis, myriocin and FB1, were extremely toxic to wild-type yeast cells expressing (WT, A53T, or E46K) a-syn but much less toxic to cells expressing A30P. The elongase mutants and ceramide synthesis inhibitors enhance the toxicity of WT a-syn, A53T and E46K, which transit through the ER, but have a negligible effect on A30P, which does not transit through the ER. Disruption of ceramide-