Title | Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Dettmer U, Newman AJ, Soldner F, Luth ES, Kim NC, von Saucken VE, Sanderson JB, Jaenisch R, Bartels T, Selkoe D |
Journal | Nat Commun |
Volume | 6 |
Pagination | 7314 |
Date Published | 2015 Jun 16 |
ISSN | 2041-1723 |
Keywords | alpha-Synuclein, Animals, Brain, Enzyme-Linked Immunosorbent Assay, Humans, Immunoblotting, Immunohistochemistry, Induced Pluripotent Stem Cells, Mice, Mutation, Missense, Neurons, Parkinson Disease, Protein Structure, Quaternary, Rats, Rats, Sprague-Dawley |
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. |
DOI | 10.1038/ncomms8314 |
Alternate Journal | Nat Commun |
PubMed ID | 26076669 |
PubMed Central ID | PMC4490410 |
Grant List | HD045022 / HD / NICHD NIH HHS / United States R37 HD045022 / HD / NICHD NIH HHS / United States R37 CA084198 / CA / NCI NIH HHS / United States 5R37 CA84198 / CA / NCI NIH HHS / United States R01 HD045022 / HD / NICHD NIH HHS / United States R01 NS083845 / NS / NINDS NIH HHS / United States |
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