Abstract
Polymorphism is a common and important phenomenon for protein fibrils which has been linked to the appearance of strains in prion and other neurodegenerative diseases. Parkinson disease is a frequently occurring neurodegenerative pathology, tightly associated with the formation of Lewy bodies. These deposits mainly consist of α-synuclein in fibrillar, β-sheet-rich form. α-synuclein is known to form numerous different polymorphs, which show distinct structural features. Here, we describe the chemical shift assignments, and derive the secondary structure, of a polymorph that was fibrillized at higher-than-physiological pH conditions. The fibrillar core contains residues 40–95, with both the C- and N-terminus not showing any ordered, rigid parts. The chemical shifts are similar to those recorded previously for an assigned polymorph that was fibrillized at neutral pH.
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References
Böckmann A, Gardiennet C, Verel R et al (2009) Characterization of different water pools in solid-state NMR protein samples. J Biomol NMR 45:319–327. doi:10.1007/s10858-009-9374-3
Bousset L, Pieri L, Ruiz-Arlandis G et al (2013) Structural and functional characterization of two alpha-synuclein strains. Nat Commun 4:2575. doi:10.1038/ncomms3575
Brundin P, Melki R, Kopito R (2010) PeRsPecTives. 1–7. doi: 10.1038/nrm2873
Cohlberg JA, Li J, Uversky VN, Fink AL (2002) Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from α-synuclein in vitro. Biochemistry 41:1502–1511. doi:10.1021/bi011711s
Comellas G, Lemkau LR, Nieuwkoop AJ et al (2011) Structured regions of α-synuclein fibrils include the early-onset Parkinson’s disease mutation sites. J Mol Biol 411:881–895. doi:10.1016/j.jmb.2011.06.026
Comellas G, Lemkau LR, Zhou DH et al (2012) Structural intermediates during α-synuclein fibrillogenesis on phospholipid vesicles. J Am Chem Soc 134:5090–5099. doi:10.1021/ja209019s
Cornilescu G, Delaglio F, Bax A (1999) Protein backbone angle restraints from searching a database for chemical shift and sequence homology. J Biomol NMR 13:289–302. doi:10.1023/A:1008392405740
Der-Sarkissian A, Jao CC, Chen J et al (2003) Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling. J Biol Chem 278:37530–37535. doi:10.1074/jbc.M305266200
Eller M, William DR (2011) α-Synuclein in Parkinson disease and other neurodegenerative disorders. Clin Chem Lab Med 49:403–408. doi:10.1515/CCLM.2011.077
Gath J, Habenstein B, Bousset L et al (2012) Solid-state NMR sequential assignments of α-synuclein. Biomol NMR Assign 6:51–55. doi:10.1007/s12104-011-9324-3
Gath J, Bousset L, Habenstein B et al (2014a) Unlike twins: an NMR comparison of two α-synuclein polymorphs featuring different toxicity. PLoS ONE 9:e90659. doi:10.1371/journal.pone.0090659
Gath J, Bousset L, Habenstein B et al (2014b) Yet another polymorph of α-synuclein: solid-state sequential assignments. Biomol NMR Assign 8:395–404. doi:10.1007/s12104-013-9526-y
Habenstein B, Wasmer C, Bousset L et al (2011) Extensive de novo solid-state NMR assignments of the 33 kDa C-terminal domain of the Ure2 prion. J Biomol NMR 51:235–243. doi:10.1007/s10858-011-9530-4
Hansen C, Angot E, Bergström AL et al (2011) α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725. doi:10.1172/JCI43366
Heise H, Hoyer W, Becker S et al (2005) Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR. Proc Natl Acad Sci USA 102:15871–15876. doi:10.1073/pnas.0506109102
Lv G, Kumar A, Giller K et al (2012) Structural comparison of mouse and human α-synuclein amyloid fibrils by solid-state NMR. J Mol Biol 420:99–111. doi:10.1016/j.jmb.2012.04.009
Miake H (2002) Biochemical characterization of the core structure of alpha-synuclein filaments. J Biol Chem 277:19213–19219. doi:10.1074/jbc.M110551200
Pawar AP, DuBay KF, Zurdo J, Chiti F, Vendruscolo M, Dobson CM (2005) Prediction of “aggregation-prone” and “aggregation-susceptible” regions in proteins associated with neurodegenerative diseases. J Mol Biol 350:379–392. doi:10.1016/j.jmb.2005.04.016
Schuetz A, Wasmer C, Habenstein B et al (2010) Protocols for the sequential solid-state NMR spectroscopic assignment of a uniformly labeled 25 kDa protein: HET-s(1-227). ChemBioChem 11:1543–1551. doi:10.1002/cbic.201000124
Stevens TJ, Fogh RH, Boucher W et al (2011) A software framework for analysing solid-state MAS NMR data. J Biomol NMR 51:437–447. doi:10.1007/s10858-011-9569-2
Acknowledgments
This work was supported by the Agence Nationale de la Recherche (ANR-11-BSV8-021-01, ANR-12-BS08-0013-01), the ETH Zurich, the Swiss National Science Foundation (Grant 200020_124611), the Era-Net Neuron (Project MIPROTRAN, ANR-08-NEUR-001-01) and the Centre National de la Recherche Scientifique. We also acknowledge support from the European Commission under the Seventh Framework Programme (FP7), contract Bio-NMR 261863.
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Joeri Verasdonck and Luc Bousset have contributed equally to this work.
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Verasdonck, J., Bousset, L., Gath, J. et al. Further exploration of the conformational space of α-synuclein fibrils: solid-state NMR assignment of a high-pH polymorph. Biomol NMR Assign 10, 5–12 (2016). https://doi.org/10.1007/s12104-015-9628-9
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DOI: https://doi.org/10.1007/s12104-015-9628-9