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

doi:10.1016/j.jmb.2011.06.026

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	881-895
Number of pages	15
Journal	Journal of Molecular Biology
Volume	411
Issue number	4
DOIs	https://doi.org/10.1016/j.jmb.2011.06.026
State	Published - 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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Structured regions of α-Synuclein fibrils include the early-onset Parkinson's disease mutation sites. / Comellas, Gemma; Lemkau, Luisel R.; Nieuwkoop, Andrew J.; Kloepper, Kathryn D.; Ladror, Daniel T.; Ebisu, Reika; Woods, Wendy S.; Lipton, Andrew S.; George, Julia M.; Rienstra, Chad M.

In: Journal of Molecular Biology, Vol. 411, No. 4, 26.08.2011, p. 881-895.

Research output: Contribution to journal › Article › peer-review

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

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.",

keywords = "Lewy bodies, conformational dynamics, magic-angle spinning, solid-state NMR, structural perturbations",

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

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AU - Kloepper, Kathryn D.

AU - Ladror, Daniel T.

AU - Ebisu, Reika

AU - Woods, Wendy S.

AU - Lipton, Andrew S.

AU - George, Julia M.

AU - Rienstra, Chad M.

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