期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms8314
关键词
-
资金
- NIH [R01 NS083845, 5R37 CA84198, HD045022]
- Fidelity Biosciences Research Initiative
- Michael J Fox Foundation
- Parkinson's Disease Foundation [PDF-IRG-1204]
beta-Sheet-rich alpha-synuclein (alpha S) aggregates characterize Parkinson's disease (PD). alpha S 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 alpha S in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant alpha S 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 alpha S repeat motifs (KTKEGV) further reduces tetramers, decreases alpha S 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.
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