A Study On The Regulation Of α-synuclein Aggregation By Lentinan

Parkinson’s disease（PD）is the second largest central nervous system degenerative disease around the world.α-Synuclein（α-Syn）is the main component of Lewy body（LB）amyloid deposits in the brain of PD patients and associated with the pathogenesis of PD.Therefore,inhibition ofα-Syn aggregation and removal of preformed amyloid fibers are important strategies for the prevention and treatment of PD.However,there is still a lack of the potent inhibitors to interfere withα-Syn aggregation.This work aims to develop agents which can effectively modulateα-Syn aggregation and disaggregate preformed amyloid aggregates.Lentinan（LNT）is a natural polysaccharide extracted from the fruit body of Lentinula edodes.It has been reported that LNT can inhibit amyloid aggregation of islet amyloid polypeptide（h IAPP）which is associated with type 2 diabetes.However,the effect of LNT onα-Syn remains unclear.In this dissertation,we demonstrate that LNT can potently preventα-Syn aggregation,disaggregate preformed amyloid aggregates and reduce cytotoxicity induced byα-Syn aggregation.We also find that the molecular weight of the polysaccharide has an impact on the inhibitory effect of LNT.At the same concentration,the inhibitory effect of low molecular weight LNT（3 KDa,LMW LNT）onα-Syn aggregation is weaker than that of the high molecular weight LNT（300 KDa,HMW LNT）.When the concentration of LMW LNT reaches 3-4 times that of HMW LNT,it exhibits similar inhibitory effect as HMW LNT.¹H-¹⁵N NMR Heteronuclear Single Quantum Coherence（HSQC）experiment results suggest that LNT interacts with N-terminus and Non-Amyloid Component（NAC）region ofα-Syn through non-specific weak interactions.Further investigation demonstrates that LNT inhibitsα-Syn aggregation in C.elegan model.The results show that LNT inhibits the accumulation ofα-Syn in nematodes,relieves the symptoms of PD nematode motility disorders,and effectively protects dopaminergic neurons from nematodes.As far as we know,this is the first time to report that LNT moderatesα-Syn aggregation in vitro and in C.elegans,which will provide new ideas for designing and developing potential agents for PD treatment.