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

Saranna Fanning, Aftabul Haque, Thibaut Imberdis, Valeriya Baru, M. Inmaculada Barrasa, Silke Nuber, Daniel Termine, Nagendran Ramalingam, Gary P.H. Ho, Tallie Noble, Jackson Sandoe, Yali Lou, Dirk Landgraf, Yelena Freyzon, Gregory Newby, Frank Soldner, Elizabeth Terry-Kantor, Tae Eun Kim, Harald F. Hofbauer, Michel BecuweRudolf Jaenisch, David Pincus, Clary B. Clish, Tobias C. Walther, Robert V. Farese, Supriya Srinivasan, Michael A. Welte, Sepp D. Kohlwein, Ulf Dettmer, Susan Lindquist, Dennis Selkoe

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1001-1014.e8
JournalMolecular Cell
Volume73
Issue number5
DOIs
StatePublished - Mar 7 2019
Externally publishedYes

Keywords

  • Parkinson's disease
  • alpha-synuclein
  • diglyceride
  • inclusions
  • lipid droplets
  • oleic acid
  • stearoyl-CoA-desaturase
  • synucleinopathy
  • tetramer
  • triglyceride
  • unsaturated fatty acid

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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