Defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson's disease.
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).
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, Louisiana, United States of America.
Yong Joo
YJ
Lee
Shaoxiao
S
Wang
Sunny R
SR
Slone
Talene A
TA
Yacoubian
Stephan N
SN
Witt
D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics*; D002518:Ceramides / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D010300:Parkinson Disease / Q000209:etiology*; D021381:Protein Transport / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D013109:Sphingomyelins / Q000096:biosynthesis; D051844:alpha-Synuclein / Q000633:toxicity*
D002518:Ceramides; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D013109:Sphingomyelins; D051844:alpha-Synuclein; D000123:Acetyltransferases; C107118:ELO2 protein, S cerevisiae
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