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

beta-Sheet-rich alpha-synuclein (alpha S) aggregates characterize Parkinson's disease (PD). alpha S was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in alpha-helix-rich tetramers. Crosslinking traps principally tetrameric alpha 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 alpha 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 alpha S repeat motifs (KTKEGV) further reduces tetramers, decreases alpha 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 alpha-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.