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.
Original language | English (US) |
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Pages (from-to) | 1001-1014.e8 |
Journal | Molecular Cell |
Volume | 73 |
Issue number | 5 |
DOIs | |
State | Published - Mar 7 2019 |
Externally published | Yes |
Keywords
- Parkinson's disease
- alpha-synuclein
- diglyceride
- inclusions
- lipid droplets
- oleic acid
- stearoyl-CoA-desaturase
- synucleinopathy
- tetramer
- triglyceride
- unsaturated fatty acid
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology