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

Author(s)
Dettmer, Ulf; Newman, Andrew J.; Soldner, Frank; Luth, Eric S.; Kim, Nora C.; von Saucken, Victoria E.; Sanderson, John B.; Jaenisch, Rudolf; Bartels, Tim; Selkoe, Dennis; ... Show more Show less
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Abstract
β-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.
Date issued
2015-06
URI
http://hdl.handle.net/1721.1/98476
Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Dettmer, 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. “Parkinson-Causing α-Synuclein Missense Mutations Shift Native Tetramers to Monomers as a Mechanism for Disease Initiation.” Nature Communications 6 (June 16, 2015): 7314. © 2015 Macmillan Publishers Limited
Version: Final published version
ISSN
2041-1723

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