title: Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson's Disease.
abstract: We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson's disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50-55% of the populations displayed normal neurons, compared to only 10-15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Shaoxiao
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, United States of America.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, United States of America.
authors.forename: Chuan
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Addie
authors.initials: A
authors.lastname: Barron
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Floyd
authors.initials: F
authors.lastname: Galiano
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, United States of America.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, United States of America.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.|Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
authors.forename: Stephan N
authors.identifier: http://orcid.org/0000-0002-6462-2840
authors.initials: SN
authors.lastname: Witt
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D002504:Meclofenoxate / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D010713:Phosphatidylcholines / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D012995:Solubility; D013426:Sulfaphenazole / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D020011:Protective Agents; D051844:alpha-Synuclein; D013426:Sulfaphenazole; C483858:phosphatidylethanolamine; D016572:Cyclosporine; D002504:Meclofenoxate; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase; D002262:Carboxy-Lyases; C577156:Psd1 protein, S cerevisiae; C022353:phosphatidylserine decarboxylase