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

Ulf Dettmer, Andrew J. Newman, Frank Soldner, Eric S. Luth, Nora C. Kim, Victoria E. Von Saucken, John B. Sanderson, Rudolf Jaenisch, Tim Bartels, Dennis Selkoe

Research output: Contribution to journalArticle

127 Citations (Scopus)

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.

Original languageEnglish (US)
Article number7314
JournalNature communications
Volume6
DOIs
StatePublished - Jun 16 2015
Externally publishedYes

Fingerprint

Synucleins
Missense Mutation
Parkinson disease
mutations
Neurons
Parkinson Disease
monomers
Monomers
neurons
shift
Brain
brain
Mutation
inclusions
pathogenesis
Crosslinking
Solubility
destabilization
crosslinking
helices

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. / Dettmer, Ulf; Newman, Andrew J.; Soldner, Frank; Luth, Eric S.; Kim, Nora C.; Von Saucken, Victoria E.; Sanderson, John B.; Jaenisch, Rudolf; Bartels, Tim; Selkoe, Dennis.

In: Nature communications, Vol. 6, 7314, 16.06.2015.

Research output: Contribution to journalArticle

Dettmer, U, Newman, AJ, Soldner, F, Luth, ES, Kim, NC, Von Saucken, VE, Sanderson, JB, Jaenisch, R, Bartels, T & Selkoe, D 2015, 'Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation', Nature communications, vol. 6, 7314. https://doi.org/10.1038/ncomms8314
Dettmer, Ulf ; Newman, Andrew J. ; Soldner, Frank ; Luth, Eric S. ; Kim, Nora C. ; Von Saucken, Victoria E. ; Sanderson, John B. ; Jaenisch, Rudolf ; Bartels, Tim ; Selkoe, Dennis. / Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. In: Nature communications. 2015 ; Vol. 6.
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