Novel Pathophysiological Roles Of α-synuclein (SNCA) In Age-related Vascular Endothelial Dysfunction: Possible Mechanistic Link To The Symptoms Of Dementia With Lewy Bodies | 106582
Journal of Alzheimers Disease & Parkinsonism
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Although SNCA is one of the well-known pathological molecules of Dementia with Lewy Bodies (DLB) in neurons, its
physiological roles remain to be identified. We found SNCA was expressed in and secreted from endothelial cells 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 vascular Endothelial Cells (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 cocultured
vascular smooth muscle cells. Treatment with rSNCA also suppressed TNF-? induced NF-?B 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 ??-gal activity along with decreased Sirt1 expression and
increased p53 expression. SNCA overexpression displayed NF-?B 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. 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 clinical features of DLB, especially fluctuating cognitive function and marked sensitivity of
antipsychotic which could be modified by cerebral blood flow and vascular permeability.
Yoichi Takami is currently working at Osaka University, Japan. He has published numerous research papers and articles in reputed journals and has various other achievements in the related studies. He has extended his valuable service towards the scientific community with his extensive research work.