Dettmer, UlfNewman, Andrew J.Soldner, FrankLuth, Eric S.Kim, Nora C.von Saucken, Victoria E.Sanderson, John B.Jaenisch, RudolfBartels, TimSelkoe, Dennis2015-08-032015Dettmer, Ulf, Andrew J. Newman, Frank Soldner, Eric S. Luth, Nora C. Kim, Victoria E. von Saucken, John B. Sanderson, Rudolf Jaenisch, Tim Bartels, and Dennis Selkoe. 2015. “Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.” Nature Communications 6 (1): 7314. doi:10.1038/ncomms8314. http://dx.doi.org/10.1038/ncomms8314.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820788β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson's disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS 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 αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS 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 α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.en-USJournal Article2015-08-0310.1038/ncomms8314