@article{60e235204a5948d7b8e2b7dec594c96c,
title = "Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment",
abstract = "In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.",
keywords = "Parkinson's disease, alpha-synuclein, diglyceride, inclusions, lipid droplets, oleic acid, stearoyl-CoA-desaturase, synucleinopathy, tetramer, triglyceride, unsaturated fatty acid",
author = "Saranna Fanning and Aftabul Haque and Thibaut Imberdis and Valeriya Baru and Barrasa, {M. Inmaculada} and Silke Nuber and Daniel Termine and Nagendran Ramalingam and Ho, {Gary P.H.} and Tallie Noble and Jackson Sandoe and Yali Lou and Dirk Landgraf and Yelena Freyzon and Gregory Newby and Frank Soldner and Elizabeth Terry-Kantor and Kim, {Tae Eun} and Hofbauer, {Harald F.} and Michel Becuwe and Rudolf Jaenisch and David Pincus and Clish, {Clary B.} and Walther, {Tobias C.} and Farese, {Robert V.} and Supriya Srinivasan and Welte, {Michael A.} and Kohlwein, {Sepp D.} and Ulf Dettmer and Susan Lindquist and Dennis Selkoe",
note = "Funding Information: We thank Linda Clayton, Luke Whitesell, Gerry Fink, Maeve Bonner, Charles Serhan, Maja Radulovic, Ian Cheeseman, Tim Bartels, Can Kayatekin, Joe Negri, Meichen Liao, and Andrew Newman for valuable discussions and input; Melissa Duquette and Molly Rajsombath for technical assistance; Hana El Samad and her lab for estradiol constructs; and Lisa Freinkman, Bena Chan, Caroline Lewis, and Tenzin Kunchok at the Metabolomics Core, Whitehead Institute for Biomedical Research. We thank Christina Muratore at the iPSC Neurohub at the Ann Romney Center for Neurologic Diseases for providing cell lines, reagents, and assistance. We are grateful to Nicole Boucher for her administrative support. Audrey Madden, Robert Burger, and Brooke Bevis provided lab support. S.D.K. was supported by the Austrian Science Fund FWF, DK Molecular Enzymology Project W901, and NAWI Graz. S.F. and S.L. were supported by the JPB Foundation. S.L. was an HHMI Investigator. This work was supported by a fellowship from the Jane Coffin Childs Memorial Fund for medical research (M.B.) and by NIH grants NS065743 (G.P.H.H.), GM102155 (M.A.W.), NS103123 (S.N.), NS099328 (U.D.), and NS083845 (D.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Much of this work was performed in the laboratory of and under the supervision of Dr. Susan Lindquist, who sadly passed away before completion of this manuscript. We recognize her significant involvement, contribution, and commitment to this work. Funding Information: We thank Linda Clayton, Luke Whitesell, Gerry Fink, Maeve Bonner, Charles Serhan, Maja Radulovic, Ian Cheeseman, Tim Bartels, Can Kayatekin, Joe Negri, Meichen Liao, and Andrew Newman for valuable discussions and input; Melissa Duquette and Molly Rajsombath for technical assistance; Hana El Samad and her lab for estradiol constructs; and Lisa Freinkman, Bena Chan, Caroline Lewis, and Tenzin Kunchok at the Metabolomics Core, Whitehead Institute for Biomedical Research. We thank Christina Muratore at the iPSC Neurohub at the Ann Romney Center for Neurologic Diseases for providing cell lines, reagents, and assistance. We are grateful to Nicole Boucher for her administrative support. Audrey Madden, Robert Burger, and Brooke Bevis provided lab support. S.D.K. was supported by the Austrian Science Fund FWF , DK Molecular Enzymology Project W901 , and NAWI Graz . S.F. and S.L. were supported by the JPB Foundation . S.L. was an HHMI Investigator. This work was supported by a fellowship from the Jane Coffin Childs Memorial Fund for medical research (M.B.) and by NIH grants NS065743 (G.P.H.H.), GM102155 (M.A.W.), NS103123 (S.N.), NS099328 (U.D.), and NS083845 (D.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Much of this work was performed in the laboratory of and under the supervision of Dr. Susan Lindquist, who sadly passed away before completion of this manuscript. We recognize her significant involvement, contribution, and commitment to this work. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2019",
month = mar,
day = "7",
doi = "10.1016/j.molcel.2018.11.028",
language = "English (US)",
volume = "73",
pages = "1001--1014.e8",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}
