MIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
  • DSpace@MIT Home
  • MIT Open Access Articles
  • MIT Open Access Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

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

Author(s)
Fanning, Saranna; Haque, Aftabul; Imberdis, Thibaut; Baru, Valeriya; Barrasa, M. Inmaculada; Nuber, Silke; Termine, Daniel; Ramalingam, Nagendran; Ho, Gary P.H.; Noble, Tallie; Sandoe, Jackson; Lou, Yali; Landgraf, Dirk; Freyzon, Yelena; Newby, Gregory; Soldner, Frank; Terry-Kantor, Elizabeth; Kim, Tae-Eun; Hofbauer, Harald F.; Becuwe, Michel; Jaenisch, Rudolf; Pincus, David; Clish, Clary B.; Walther, Tobias C.; Farese, Robert V.; Srinivasan, Supriya; Welte, Michael A.; Kohlwein, Sepp D.; Dettmer, Ulf; Lindquist, Susan; Selkoe, Dennis; ... Show more Show less
Thumbnail
DownloadAccepted version (2.212Mb)
Publisher with Creative Commons License

Publisher with Creative Commons License

Creative Commons Attribution

Terms of use
Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/
Metadata
Show full item record
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; synucleinopathy; alpha-synuclein; stearoyl-CoA-desaturase; unsaturated fatty acid; oleic acid; lipid droplets; diglyceride; triglyceride; tetramer; inclusions
Date issued
2018-12
URI
https://hdl.handle.net/1721.1/125128
Department
Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology. Department of Biology; Broad Institute of MIT and Harvard
Journal
Molecular Cell
Publisher
Elsevier BV
Citation
Fanning, Saranna et al. "Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment." Molecular Cell 73, 5 (March 2019): 1001-1014 © 2018 Elsevier Inc.
Version: Author's final manuscript
ISSN
1097-2765

Collections
  • MIT Open Access Articles

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries
PrivacyPermissionsAccessibilityContact us
MIT
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.