Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.
| Publication Type | Academic Article |
| Authors | Dettmer U, Newman A, Soldner F, Luth E, Kim N, von Saucken V, Sanderson J, Jaenisch R, Bartels T, Selkoe D |
| Journal | Nat Commun |
| Volume | 6 |
| Pagination | 7314 |
| Date Published | 06/16/2015 |
| ISSN | 2041-1723 |
| Keywords | Brain, Neurons, Parkinson Disease, alpha-Synuclein |
| 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 |
| PubMed ID | 26076669 |
| PubMed Central ID | PMC4490410 |