Abstract
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).
Highlights
Alpha-synuclein (a-syn) is a neuronal protein that has been linked to Parkinson’s disease (PD) by biochemical and genetic studies [1]
Strains were transformed with a high copy plasmid containing a-syn under control of the gal promoter, serially diluted on plates with inducing media (+gal), and scored for growth inhibition compared to the uninduced condition (-gal)
We focused on characterizing the ELO genes that code for membrane-bound enzymes of the endoplasmic reticulum (ER) that elongate medium chain fatty acids to C26-VLCFA
Summary
Alpha-synuclein (a-syn) is a neuronal protein that has been linked to Parkinson’s disease (PD) by biochemical and genetic studies [1]. Alterations in a-syn cause the degeneration of dopaminergic neurons in an area of the mid-brain called the substantia nigra pars compacta [2,3]. Loss of these neurons results in slowness of movement, resting tremor, rigidity, and disturbances of gait and posture [1,4,5], which are the clinical manifestations of PD. Only 10% of all PD cases are due to specific mutations in these genes, whereas 90% of the cases are ‘‘sporadic’’, meaning there is no known cause, a-syn probably is connected to these cases Environmental risk factors such as exposure to heavy metals or pesticides may make a-syn more toxic. The unifying concept is that Parkinson’s disease occurs in some individuals but not others because of an age-related decrement in the mechanisms that naturally protect cells from toxic alterations in a-syn
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