The Role Of Α-Synuclein In Brain Lipid Metabolism And Inflammation

Alpha-synuclein (Snca) is a small cytosolic protein that is ubiquitously expressed in the nervous system and comprises 0.5-1% of all cytosolic protein, but its biological function is poorly understood. Although Snca function has been studied in lipid metabolism, the function of Snca in brain lipid metabolism under inflammatory conditions is yet to be elucidated. We utilized several model systems including primary cultured astrocytes and microglia, Snca deficient and mutant knock-in mice, and a radiolabeled free fatty acid steady state-kinetic mouse model to determine Snca role in neuroinflammation. Herein, we have determined several major roles of Snca during inflammation: (i) dBcAMP treatment increases 20:4n-6 uptake in astrocytes and this increase appears to be due to increased expression of long chain acyl-CoA synthetases 3 and -4 coupled with a reduction in acyl-CoA hydrolase expression in the presence of reduced Snca expression. (ii) Snca deficient mice have higher basal brain 2-arachidonyl glycerol (2-AG) levels compared to wildtype and lipopolysaccharide (LPS) stimulation further exacerbated 2-AG synthesis.(iii) In primary microglia, LPS-treatment reduced released 2-AG into medium concomitantly with reduced Snca expression and Snca deficient microglia had a delayed response to LPS stimuli. This supports the hypothesis that Snca expression is linked to 2-AG release in primary microglia and may contribute to regulating the phagocytic phenotype.(iv) Using Snca gene-ablated mice, we determined the impact of Snca on brain 20:4n-6 metabolism during LPS-induced inflammatory response in vivo using an established steady-state kinetic model. In Snca deficient mouse brain, 20:4n-6 uptake was significantly increased 1.3-fold. In the organic fraction, tracer entering into Snca deficient mouse total brain phospholipids was significantly increased 1.4-fold, accounted for by increased incorporation into choline glycerophospholipids and phosphatidylinositol. In the neutral lipid fraction, 20:4n-6 incorporation into diacylglycerol of Snca deficient mice was significantly reduced by 75%. Hence, under inflammatory conditions where 20:4n-6 release is enhanced, Snca has a crucial role in modulating 20:4n-6 metabolism, and the absence of Snca results in increased uptake and incorporation into lipid pools associated with enhanced lipid-mediated signaling during neuroinflammatory response. Herein, we focus on the role of Snca in downstream eicosanoid biosynthesis, inflammatory mediators, and lipid signaling molecules linking Snca to inflammatory response elucidating a key step in neuroinflammation