| First Author | Fanning S | Year | 2019 |
| Journal | Mol Cell | Volume | 73 |
| Issue | 5 | Pages | 1001-1014.e8 |
| PubMed ID | 30527540 | Mgi Jnum | J:273662 |
| Mgi Id | MGI:6282766 | Doi | 10.1016/j.molcel.2018.11.028 |
| Citation | Fanning S, et al. (2019) Lipidomic Analysis of alpha-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell 73(5):1001-1014.e8 |
| abstractText | In Parkinson's disease (PD), alpha-synuclein (alphaS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in alphaS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human alphaS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of alphaS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased alphaS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in alphaS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented alphaS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on alphaS homeostasis: in human neural cells, excess OA caused alphaS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for alphaS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach. |
