title: Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease.
abstract: Phosphatidylserine decarboxylase, which is embedded in the inner mitochondrial membrane, synthesizes phosphatidylethanolamine (PE) and, in some cells, synthesizes the majority of this important phospholipid. Normal levels of PE can decline with age in the brain. Here we used yeast and worms to test the hypothesis that low levels of PE alter the homeostasis of the Parkinson disease-associated protein α-synuclein (α-syn). In yeast, low levels of PE in the phosphatidylserine decarboxylase deletion mutant (psd1Δ) cause decreased respiration, endoplasmic reticulum (ER) stress, a defect in the trafficking of the uracil permease, α-syn accumulation and foci, and a slow growth phenotype. Supplemental ethanolamine (ETA), which can be converted to PE via the Kennedy pathway enzymes in the ER, had no effect on respiration, whereas, in contrast, this metabolite partially eliminated ER stress, decreased α-syn foci formation, and restored growth close to that of wild-type cells. In Caenorhabditis elegans, RNAi depletion of phosphatidylserine decarboxylase in dopaminergic neurons expressing α-syn accelerates neurodegeneration, which supplemental ETA rescues. ETA fails to rescue this degeneration in worms that undergo double RNAi depletion of phosphatidylserine decarboxylase (psd-1) and choline/ETA phosphotransferase (cept-1), which encodes the last enzyme in the CDP-ETA Kennedy pathway. This finding suggests that ETA exerts its protective effect by boosting PE through the Kennedy pathway. Overall, a low level of PE causes ER stress, disrupts vesicle trafficking, and causes α-syn to accumulate; such cells likely die from a combination of ER stress and excessive accumulation of α-syn.
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Shaoxiao
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487; and.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071.
authors.forename: Liang-Chun
authors.initials: LC
authors.lastname: Liou
authors.affiliation: Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071.
authors.forename: Qun
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071.
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487; and.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487; and.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.affiliation: Departments of Biochemistry and Molecular Biology and Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130; switt1@lsuhsc.edu.
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Witt
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D006706:Homeostasis; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010714:Phosphatidylethanolamines; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D024101:Mitochondrial Proteins; D010714:Phosphatidylethanolamines; D051844:alpha-Synuclein; C483858:phosphatidylethanolamine; D002262:Carboxy-Lyases; C577156:Psd1 protein, S cerevisiae
keywords: aging; lipid disequilibrium; proteinopathy