Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship betw...Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship between a-synuclein self-assembly and Lewy body formation remains unclear.Here,we show,both in vitro and in a Caenorhabditis elegans model of PD,thatα-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state,which converts into an amyloid-rich hydrogel with Lewy-body-like properties.This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro.Taken together,these results suggest that the formation of Lewy bodies may be linked to the arrested maturation ofα-synuclein condensates in the presence of lipids and other cellular components.展开更多
基金G.S.K.S.acknowledges funding from the Wellcome Trust(065807/Z/01/Z and 203249/Z/16/Z)the UK Medical Research Council(MRC,MR/K02292X/1)+2 种基金Alzheimer Research UK(ARUK,ARUK-PG013-14)Michael J Fox Foundation(16238)from Infinitus China Ltd.S.T.D.acknowledges funding from the Biotechnology and Biological Sciences Research Council(BBSRC,BB/M011194/1).
文摘Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship between a-synuclein self-assembly and Lewy body formation remains unclear.Here,we show,both in vitro and in a Caenorhabditis elegans model of PD,thatα-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state,which converts into an amyloid-rich hydrogel with Lewy-body-like properties.This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro.Taken together,these results suggest that the formation of Lewy bodies may be linked to the arrested maturation ofα-synuclein condensates in the presence of lipids and other cellular components.
