Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment PMID: 30527540

ADC Targets in Oncology

2026-04-10

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

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: [email protected].
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: [email protected].

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.