b-Sheet-rich @entity8095 (aS) aggregates characterize @entity191 ( @entity191 ). aS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in a-helix-rich tetramers. Crosslinking traps principally tetrameric aS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal @entity1 brain contains abundant aS tetramers. The @entity191 -causing mutation @entity20098 decreases tetramers in @entity19 brain. Neurons derived from an @entity20098 @entity1 have decreased tetramers. Neurons expressing @entity34716 do also, and adding 1-2 @entity34716 -like mutations into the canonical aS repeat motifs (KTKEGV) further reduces tetramers, decreases aS solubility and induces @entity2359 and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by @entity191 -causing missense mutations and the @entity2359 and inclusions induced by markedly decreasing tetramers suggest that decreased a-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.

Parkinson-causing XXXX missense mutations shift native tetramers to monomers as a mechanism for disease initiation.

@entity1 :: ('9606', 'Species') :: ['human', 'patient'] @entity34716 :: ('p|SUB|E|46|K', 'ProteinMutation') :: ['E46K'] @entity8095 :: ('6622', 'Gene') :: ['a-synuclein'] @entity19 :: ('10090', 'Species') :: ['mouse'] @entity191 :: ('MESH:D010300', 'Disease') :: ["Parkinson's disease", 'PD'] @entity20098 :: ('c|SUB|A|53|T', 'DNAMutation') :: ['A53T'] @entity2359 :: ('MESH:D020258', 'Disease') :: ['neurotoxicity']
@entity8095 :: (6622,Gene) :: ['a-synuclein']
