NOVEL PATHOPHYSIOLOGICAL ROLES OF ALPHA-SYNUCLEIN (SNCA) IN AGE-RELATED VASCULAR ENDOTHELIAL DYSFUNCTION

Abstract

Objective: Although SNCA is one of the well-known pathological molecule of synucleinopathy in neurons, its physiological roles remain to be identified. In the present study, we sought to elucidate the novel functions of SNCA in endothelium. Design and method: Analysis for human samples, in vitro experiments using endothelial cells (ECs), and in vivo investigation using SNCA knockout or SNCA/ApoE double knockout mice were performed. Results: We found SNCA was expressed in and secreted from ECs by functional screening for anti-inflammatory molecules and detectable in circulating blood. Intriguingly, the human population study revealed serum SNCA levels decreased with aging and displayed inverse correlation with blood pressure and insulin sensitivity, which indicated protective properties of circulating SNCA on vascular endothelial function. Furthermore, we also found SNCA knockout mice displayed phenotypes of metabolic syndrome such as hypertension, impaired glucose metabolism, and dyslipidemia. Based on these preliminary data, we sought to elucidate the physiological functions of endogenous and exogenous SNCA for ECs. Exogenous treatment with recombinant SNCA (rSNCA) promoted eNOS activation and nitric oxide production via Gab1/PI3K/Akt pathway in ECs, followed by cGMP production in co-cultured vascular smooth muscle cells. Treatment with rSNCA also suppressed TNF-alpha induced NF-kappaB activation in ECs. As to endogenous SNCA, replicative senescence showed attenuation of SNCA expression in ECs and siRNA-mediated silencing of SNCA induced eNOS inactivation and cell senescence assessed by beta-gal activity along with decreased Sirt1 expression and increased p53 expression. SNCA overexpression displayed NF-kappaB inactivation in ECs. In ex vivo study, aortas from SNCA knockout mice showed impairment of acetylcholine-induced relaxation possibly due to eNOS dysfunction. In in vivo study utilizing atherosclerosis model of SNCA/ApoE double-knockout mice showed exaggerated expression of inflammatory genes which play important roles in atherogenesis. Conclusions: In conclusion, these results indicate exogenous and endogenous SNCA in ECs might physiologically maintain cerebral vascular integrity. Aging or aggregation-related loss-of-function of SNCA in ECs might be partially correlated with age-related hypertension or clinical features of dementia with Lewy body such as fluctuating cognitive function and marked sensitivity of antipsychotic which could be modified by cerebral blood flow and vascular permeability.