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

ABSTRACT: ?-Sheet-rich ?-synuclein (?S) aggregates characterize Parkinson's disease (PD). ?S was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in ?-helix-rich tetramers. Crosslinking traps principally tetrameric ?S in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant ?S tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical ?S repeat motifs (KTKEGV) further reduces tetramers, decreases ?S solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased ?-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.

SUBMITTER: Dettmer U 

PROVIDER: S-EPMC4490410 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other