1. Academic Validation
  2. Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

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

  • Mol Cell. 2019 Mar 7;73(5):1001-1014.e8. doi: 10.1016/j.molcel.2018.11.028.
Saranna Fanning 1 Aftabul Haque 2 Thibaut Imberdis 3 Valeriya Baru 2 M Inmaculada Barrasa 2 Silke Nuber 3 Daniel Termine 2 Nagendran Ramalingam 3 Gary P H Ho 3 Tallie Noble 4 Jackson Sandoe 2 Yali Lou 2 Dirk Landgraf 2 Yelena Freyzon 2 Gregory Newby 5 Frank Soldner 2 Elizabeth Terry-Kantor 3 Tae-Eun Kim 3 Harald F Hofbauer 6 Michel Becuwe 7 Rudolf Jaenisch 5 David Pincus 2 Clary B Clish 8 Tobias C Walther 9 Robert V Farese Jr 10 Supriya Srinivasan 11 Michael A Welte 12 Sepp D Kohlwein 6 Ulf Dettmer 13 Susan Lindquist 14 Dennis Selkoe 15
Affiliations

Affiliations

  • 1 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 2 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 3 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 4 Mira Costa College, 1 Barnard Drive, Oceanside, CA 92056, USA.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
  • 6 Institute of Molecular Biosciences, BioTechMed-Graz, University of Graz, 8010 Graz, Austria.
  • 7 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 9 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; HHMI, Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.
  • 10 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • 11 Department of Chemical Physiology and The Dorris Neuroscience Center, 1 Barnard Drive, Oceanside, CA 92056, USA; The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 12 Department of Biology, University of Rochester, Rochester, NY 14627, USA.
  • 13 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: udettmer@bwh.harvard.edu.
  • 14 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; HHMI, Department of Biology, MIT, Cambridge, MA 02139, USA.
  • 15 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: dselkoe@bwh.harvard.edu.
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.

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