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

ABSTRACT: In Parkinson's disease (PD), ?-synuclein (?S) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in ?S or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human ?S-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of ?S dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased ?S yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in ?S-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented ?S-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on ?S homeostasis: in human neural cells, excess OA caused ?S inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for ?S-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.

SUBMITTER: Fanning S 

PROVIDER: S-EPMC6408259 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature