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Structured regions of ?-synuclein fibrils include the early-onset Parkinson's disease mutation sites.

ABSTRACT: ?-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 ?-strands of the wild-type fibrils, are associated with major and minor structural perturbations, respectively.

SUBMITTER: Comellas G 

PROVIDER: S-EPMC3157309 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Comellas Gemma G   Lemkau Luisel R LR   Nieuwkoop Andrew J AJ   Kloepper Kathryn D KD   Ladror Daniel T DT   Ebisu Reika R   Woods Wendy S WS   Lipton Andrew S AS   George Julia M JM   Rienstra Chad M CM  

Journal of molecular biology 20110621 4

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  ...[more]