Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment
Author(s)Fanning, Saranna; Haque, Aftabul; Imberdis, Thibaut; Baru, Valeriya; Barrasa, M. Inmaculada; Nuber, Silke; Termine, Daniel; Ramalingam, Nagendran; Ho, Gary P.H.; Noble, Tallie; Sandoe, Jackson; Lou, Yali; Landgraf, Dirk; Freyzon, Yelena; Newby, Gregory; Soldner, Frank; Terry-Kantor, Elizabeth; Kim, Tae-Eun; Hofbauer, Harald F.; Becuwe, Michel; Jaenisch, Rudolf; Pincus, David; Clish, Clary B.; Walther, Tobias C.; Farese, Robert V.; Srinivasan, Supriya; Welte, Michael A.; Kohlwein, Sepp D.; Dettmer, Ulf; Lindquist, Susan; Selkoe, Dennis; ... Show more Show less
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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; synucleinopathy; alpha-synuclein; stearoyl-CoA-desaturase; unsaturated fatty acid; oleic acid; lipid droplets; diglyceride; triglyceride; tetramer; inclusions
DepartmentWhitehead Institute for Biomedical Research; Massachusetts Institute of Technology. Department of Biology; Broad Institute of MIT and Harvard
Fanning, Saranna et al. "Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment." Molecular Cell 73, 5 (March 2019): 1001-1014 © 2018 Elsevier Inc.
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