@article{621615fc14264c2f8b9507e5a8c73f2f,
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.}",
note = "Funding Information: All authors have approved the submission of this manuscript and have no conflicts of interest. This work was supported by the National Institutes of Health ( R01-GM073770 , R01-GM073770 ARRA supplement and NCRR Instruments grant S10 RR025037-01 ). Gemma Comellas was a Caja Madrid Foundation Graduate Fellow. A portion of the research was performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the Department of Energy's Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory. Electron micrographs were carried out in the Frederick Seitz Materials Research Laboratory Central Facilities, University of Illinois, which are partially supported by the U.S. Department of Energy under grants DE-FG02-07ER46453 and DE-FG02-07ER46471 . The authors thank Dr. Robert Tycko for advice regarding fibril rehydration, Dr. Lou A. Miller for help and advice regarding EM, Dr. Benjamin J. Wylie for help and advice with the data fitting, Lindsay J. Sperling for discussion about the NMR experiments, and Dr. Anna E. Nesbitt for careful reading and discussions of the manuscript. ",
year = "2011",
month = aug,
day = "26",
doi = "10.1016/j.jmb.2011.06.026",
language = "English (US)",
volume = "411",
pages = "881--895",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "4",
}