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 Becuwe; Rudolf Jaenisch; David Pincus; Clary B Clish; Tobias C Walther; Robert V Farese Jr; Supriya Srinivasan; Michael A Welte; Sepp D Kohlwein; Ulf Dettmer; Susan Lindquist; Dennis Selkoe

doi:10.1016/j.molcel.2018.11.028

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. Epub 2018 Dec 4.

Authors

Saranna Fanning¹, Aftabul Haque², Thibaut Imberdis³, Valeriya Baru², M Inmaculada Barrasa², Silke Nuber³, Daniel Termine², Nagendran Ramalingam³, Gary P H Ho³, Tallie Noble⁴, Jackson Sandoe², Yali Lou², Dirk Landgraf², Yelena Freyzon², Gregory Newby⁵, Frank Soldner², Elizabeth Terry-Kantor³, Tae-Eun Kim³, Harald F Hofbauer⁶, Michel Becuwe⁷, Rudolf Jaenisch⁵, David Pincus², Clary B Clish⁸, Tobias C Walther⁹, Robert V Farese Jr¹⁰, Supriya Srinivasan¹¹, Michael A Welte¹², Sepp D Kohlwein⁶, Ulf Dettmer¹³, Susan Lindquist¹⁴, Dennis Selkoe¹⁵

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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
Diglycerides / metabolism
Disease Models, Animal
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / enzymology
Dopaminergic Neurons / pathology
Drug Discovery / methods*
Enzyme Inhibitors / pharmacology*
Humans
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / enzymology
Induced Pluripotent Stem Cells / pathology
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 / metabolism
Parkinson Disease / drug therapy*
Parkinson Disease / enzymology
Parkinson Disease / genetics
Parkinson Disease / pathology
Rats, Sprague-Dawley
Saccharomyces cerevisiae / drug effects
Saccharomyces cerevisiae / enzymology
Saccharomyces cerevisiae / genetics
Stearoyl-CoA Desaturase / antagonists & inhibitors*
Stearoyl-CoA Desaturase / metabolism
Triglycerides / metabolism
alpha-Synuclein / genetics
alpha-Synuclein / toxicity*

Substances

Antiparkinson Agents
Diglycerides
Enzyme Inhibitors
Triglycerides
alpha-Synuclein
Oleic Acid
Stearoyl-CoA Desaturase

Abstract

Publication types

MeSH terms

Substances

Grants and funding