Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

• Published in: Molecular cell Vol. 73; no. 5; pp. 1001 - 1014.e8
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-03-2019
• Subjects: alpha-synuclein; alpha-Synuclein - genetics; alpha-Synuclein - toxicity; Animals; Antiparkinson Agents - pharmacology; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - enzymology; Caenorhabditis elegans - genetics; Cell Line; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Cerebral Cortex - pathology; diglyceride; Diglycerides - metabolism; Disease Models, Animal; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - enzymology; Dopaminergic Neurons - pathology; Drug Discovery - methods; Enzyme Inhibitors - pharmacology; Humans; inclusions; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - enzymology; Induced Pluripotent Stem Cells - pathology; lipid droplets; Lipid Droplets - drug effects; Lipid Droplets - enzymology; Lipid Metabolism - drug effects; Metabolomics - methods; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Nerve Degeneration; Neural Stem Cells - drug effects; Neural Stem Cells - enzymology; Neural Stem Cells - pathology; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; oleic acid; Oleic Acid - metabolism; Parkinson Disease - drug therapy; Parkinson Disease - enzymology; Parkinson Disease - genetics; Parkinson Disease - pathology; Parkinson’s disease; Rats, Sprague-Dawley; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Stearoyl-CoA Desaturase - antagonists & inhibitors; Stearoyl-CoA Desaturase - metabolism; stearoyl-CoA-desaturase; synucleinopathy; tetramer; triglyceride; Triglycerides - metabolism; unsaturated fatty acid; synucleinopathy; triglyceride; unsaturated fatty acid; oleic acid; diglyceride; alpha-synuclein; lipid droplets; tetramer; Parkinson’s disease; stearoyl-CoA-desaturase; inclusions
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2018.11.028

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.
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•αS impacts lipid homeostasis, triggering excess oleic acid (OA) and diglycerides (DG)•Triglycerides and lipid droplets protect against toxicity by sequestering OA and DG•Stearoyl-CoA desaturase (SCD) inhibition rescues αS toxicity and neuron degeneration•SCD inhibition decreases αS inclusions and increases αS multimerization and solubility
α-synuclein is an abundant nerve cell component that forms abnormal aggregates in Parkinson’s disease and other fatal brain disorders. No disease-modifying drugs are available. Here, we identify new drug targets in lipid pathways and describe how cellular lipid alterations drive α-synuclein toxicity.