Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment.
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.
|Year of Publication||
2019 Mar 07
|PubMed Central ID||
R25 NS065743 / NS / NINDS NIH HHS / United States
R01 GM102155 / GM / NIGMS NIH HHS / United States
R01 NS109510 / NS / NINDS NIH HHS / United States
RF1 NS083845 / NS / NINDS NIH HHS / United States
R01 NS099328 / NS / NINDS NIH HHS / United States
R01 NS083845 / NS / NINDS NIH HHS / United States
DP5 OD017941 / OD / NIH HHS / United States
R21 NS103123 / NS / NINDS NIH HHS / United States