Structured regions of α-Synuclein fibrils include the early-onset Parkinson's disease mutation sites

Gemma Comellas, Luisel R. Lemkau, Andrew J. Nieuwkoop, Kathryn D. Kloepper, Daniel T. Ladror, Reika Ebisu, Wendy S. Woods, Andrew S. Lipton, Julia M. George, Chad M. Rienstra

Research output: Contribution to journalArticlepeer-review

Abstract

α-Synuclein (AS) fibrils are the major component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD). Here, we use results from an extensive investigation employing solid-state NMR to present a detailed structural characterization and conformational dynamics quantification of full-length AS fibrils. Our results show that the core extends with a repeated structural motif. This result disagrees with the previously proposed fold of AS fibrils obtained with limited solid-state NMR data. Additionally, our results demonstrate that the three single point mutations associated with early-onset PD-A30P, E46K and A53T-are located in structured regions. We find that E46K and A53T mutations, located in rigid β-strands of the wild-type fibrils, are associated with major and minor structural perturbations, respectively.

Original languageEnglish (US)
Pages (from-to)881-895
Number of pages15
JournalJournal of Molecular Biology
Volume411
Issue number4
DOIs
StatePublished - Aug 26 2011

Keywords

  • Lewy bodies
  • conformational dynamics
  • magic-angle spinning
  • solid-state NMR
  • structural perturbations

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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