Defects in Very Long Chain Fatty Acid Synthesis Enhance Alpha-Synuclein Toxicity in a Yeast Model of Parkinsons DiseaseReport as inadecuate




Defects in Very Long Chain Fatty Acid Synthesis Enhance Alpha-Synuclein Toxicity in a Yeast Model of Parkinsons Disease - Download this document for free, or read online. Document in PDF available to download.

We identified three S. cerevisiae lipid elongase null mutants elo1Δ, elo2Δ, and elo3Δ that enhance the toxicity of alpha-synuclein α-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 α-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 α-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 α-syn but much less toxic to cells expressing A30P. The elongase mutants and ceramide synthesis inhibitors enhance the toxicity of WT α-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-sphingolipid homeostasis in the ER dramatically enhances the toxicity of α-syn WT, A53T, and E46K.



Author: Yong Joo Lee, Shaoxiao Wang, Sunny R. Slone, Talene A. Yacoubian, Stephan N. Witt

Source: http://plos.srce.hr/



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