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

Nat Commun. 2015 Jun 16;6:7314. doi: 10.1038/ncomms8314.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Induced Pluripotent Stem Cells
  • Mice
  • Mutation, Missense
  • Neurons / metabolism*
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Protein Structure, Quaternary / genetics
  • Rats
  • Rats, Sprague-Dawley
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism

Substances

  • SNCA protein, human
  • Snca protein, mouse
  • Snca protein, rat
  • alpha-Synuclein