| First Author | Dettmer U | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 7314 | PubMed ID | 26076669 |
| Mgi Jnum | J:223029 | Mgi Id | MGI:5646346 |
| Doi | 10.1038/ncomms8314 | Citation | Dettmer U, et al. (2015) Parkinson-causing alpha-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun 6:7314 |
| abstractText | beta-Sheet-rich alpha-synuclein (alphaS) aggregates characterize Parkinson's disease (PD). alphaS 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 alphaS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant alphaS 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 alphaS repeat motifs (KTKEGV) further reduces tetramers, decreases alphaS 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. |
