Cited by 297Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsLipid metabolism and biosynthesis

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

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Fanning, Saranna, Haque, Aftabul, Imberdis, Thibaut, Baru, Valeriya, Barrasa, M. Inmaculada, Nuber, Silke, Termine, Daniel, Ramalingam, Nagendran +23 more·2019·Molecular Cell

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.

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Authors
Fanning, S., Haque, A., Imberdis, T., Baru, V., Barrasa, M. I., Nuber, S., Termine, D., Ramalingam, N., Ho, G. P. H., Noble, T., Sandoe, J., Lou, Y., Landgraf, D., Freyzon, Y., Newby, G., Soldner, F., Terry-Kantor, E., Kim, T.-E., Hofbauer, H. F., Becuwe, M., Jaenisch, R., Pincus, D., Clish, C. B., Walther, T. C., Farese, R. V., Srinivasan, S., Welte, M. A., Kohlwein, S. D., Dettmer, U., Lindquist, S., & Selkoe, D.
Affiliations
  • Brigham and Women's Hospital (US)
  • Whitehead Institute for Biomedical Research (US)
  • MiraCosta College (US)
  • University of Graz (AT)
  • Harvard University (US)
  • Broad Institute (US)
  • Howard Hughes Medical Institute (US)
  • Scripps Research Institute (US)
  • University of Rochester (US)
Corresponding author
  • Dettmer, Ulf
  • Selkoe, Dennis
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2019-03
Volume
73
Issue
5
Pages
1001-1014.e8
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2902875229
Cited by
285
References
95
Citations by year
2026: 32 · 2025: 40 · 2024: 46 · 2023: 33 · 2022: 35 · 2021: 43 · 2020: 39 · 2019: 17
FWCI
16.77
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
  • PMC
Funders
  • Austrian Science Fund FWF
  • DK Molecular Enzymology Project (W901)
  • NAWI Graz
  • JPB Foundation
  • HHMI
  • Jane Coffin Childs Memorial Fund
  • NIH (NS065743, GM102155, NS103123, NS099328, NS083845)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
alpha-synuclein, Parkinson's disease, stearoyl-CoA desaturase, oleic acid, lipidomics, neurotoxicity, lipid droplets, monounsaturated fatty acids, fatty acid metabolism, alpha-synuclein aggregation, dopaminergic neurons, therapeutic target
MeSH terms
Animals, Antiparkinson Agents, Cell Line, Cerebral Cortex, Diglycerides, Disease Models, Animal, Enzyme Inhibitors, Humans, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Parkinson Disease, Saccharomyces cerevisiae, Stearoyl-CoA Desaturase, Triglycerides, Caenorhabditis elegans, Rats, Sprague-Dawley, Oleic Acid, Lipid Metabolism, alpha-Synuclein, Metabolomics, Drug Discovery, Induced Pluripotent Stem Cells, Neural Stem Cells, Molecular Targeted Therapy, Dopaminergic Neurons, Lipid Droplets

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