Genetic Silencing of Fatty Acid Desaturases Modulates α-Synuclein Toxicity and Neuronal Loss in Parkinson-Like Models of C. elegans

Abstract

The molecular basis of Parkinson’s disease (PD) is currently unknown. There is increasing evidence that fat metabolism is at the crossroad of key molecular pathways associated with the pathophysiology of PD. Fatty acid desaturases catalyze synthesis of saturated fatty acids from monounsaturated fatty acids thereby mediating several cellular mechanisms that are associated with diseases including cancer and metabolic disorders. The role of desaturases in modulating age-related neurodegenerative manifestations such as PD is poorly understood. Here, we investigated the effect of silencing Δ9 desaturase enzyme encoding fat-5 and fat-7 genes which are known to reduce fat content, on α-synuclein expression, neuronal morphology and dopamine-related behaviors in transgenic PD-like models of Caenorhabditis elegans (C. elegans) . The silencing of the fat-5 and fat-7 genes rescued both degeneration of dopamine neurons and deficits in dopamine-dependent behaviors, including basal slowing and ethanol avoidance in worm models of PD. Similarly, silencing of these genes also decreased the formation of protein aggregates in a nematode model of PD expressing α-synuclein in the body wall muscles and rescued deficits in resistance to heat and osmotic stress. On the contrary, silencing of nhr-49 and tub-1 genes that are known to increase total fat content did not alter behavioral and pathological endpoints in the PD worm strains. Interestingly, the genetic manipulation of all four selected genes resulted in differential fat levels in the PD models without having significant effect on the lifespan, further indicating a complex fat homeostasis unique to neurodegenerative pathophysiology. Overall, we provide a comprehensive understanding of how Δ9 desaturase can alter PD-like pathology due to environmental exposures and proteotoxic stress, suggesting new avenues in deciphering the disease etiology and possible therapeutic targets.

Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson’s Disease

“…Unbiased lipidomic analyses of cells or mice expressing toxic α-synuclein showed that accumulation of lipid droplets, unsaturated fatty acids, and triglycerides is a conserved pathological feature of α-synuclein models from yeast through mice [7]. The ability of SCD inhibition to mitigate α-synuclein toxicity phenotypes in multiple independent reports and disease models speaks to the robustness of the protective benefit of reducing monounsaturated fatty acids [5,[7][8][9][10]. Recent electron microscopic evaluation of Lewy body pathology in Parkinson's disease has identified early-stage Lewy bodies to consist of membranous organelles with aggregated α-synuclein [11].…”

Anti-Parkinson Effects of Holothuria leucospilota-Derived Palmitic Acid in Caenorhabditis elegans Model of Parkinson’s Disease

“…HLEA-P3 treatments at doses of 5 and 25 μg/mL significantly reduced lipid deposition to 54.13% and 54.87%, respectively ( p < 0.05) ( Figure 5 A,B). Silencing of stearoyl-CoA desaturase-1 (SCD-1), a key enzyme in fatty acid metabolism, was shown to reduce lipid content and α-synuclein-induced neurotoxicity [ 27 ]. This study examined whether HLEA-P3 downregulated fat-5 , fat-6 and fat-7 (SCD-1 homolog) in NL5901 worms ( Figure 5 C).…”

Excess membrane binding of monomeric alpha-, beta- and gamma-synuclein is invariably associated with inclusion formation and toxicity

“…This prompted us to speculate about a bi-directional scenario in which αS leads to elevated OA levels, which—after incorporation into membrane lipids—increase αS membrane association and toxicity ( 43 ). Indeed, we and others have demonstrated that loss/inhibition of the OA-generating enzyme stearoyl-CoA desaturase (SCD) rescues αS-related toxicity in yeast ( 41 , 44 ), Caenorhaditis elegans ( 41 , 45 ), primary rodent neurons ( 41 ) and neuroblastoma cells ( 42 ). The increased cellular viability was found to be accompanied by the following changes in αS homeostasis: (1) αS serine-129 phosphorylation of αS E46K and excess wt αS was reduced upon SCD inhibition ( 41 , 42 ); (2) αS E46K solubility, as assessed by cytosol:membrane ratio in sequential extraction experiments, was increased ( 41 , 42 ) and (3) inclusion formation of αS 3K (amplified E46K) was reduced ( 41 , 42 ).…”