Reference: Lee YJ, et al. (2011) Defects in very long chain Fatty Acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson's disease. PLoS One 6(1):e15946

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Abstract


We identified three S. cerevisiae lipid elongase null mutants (elo1Delta, elo2Delta, and elo3Delta) that enhance the toxicity of alpha-synuclein (alpha-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 alpha-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) alpha-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) alpha-syn but much less toxic to cells expressing A30P. The elongase mutants and ceramide synthesis inhibitors enhance the toxicity of WT alpha-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 alpha-syn (WT, A53T, and E46K).

Reference Type
Journal Article
Authors
Lee YJ, Wang S, Slone SR, Yacoubian TA, Witt SN
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