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The differential solvent exposure of N-terminal residues provides ‘fingerprints’ of alpha-synuclein fibrillar polymorphs

Abstract : Synucleinopathies are neurodegenerative diseases characterized by the presence of intracellular deposits containing the protein alpha-synuclein (aSYN) within patients’ brains. It has been shown that aSYN can form structurally distinct fibrillar assemblies, also termed polymorphs. We previously showed that distinct aSYN polymorphs assembled in vitro, named fibrils, ribbons and fibrils 91, differentially bind to and seed the aggregation of endogenous aSYN in neuronal cells, which suggests that distinct synucleinopathies may arise from aSYN polymorphs. In order to better understand the differential interactions of aSYN polymorphs with their partner proteins, we mapped aSYN polymorphs surfaces. We used limited proteolysis, hydrogen-deuterium exchange, and differential antibody accessibility to identify amino-acids on their surfaces. We showed that the aSYN Cterminal region spanning residues 94-140 exhibited similarly high solvent accessibility in these three polymorphs. However, the N-terminal amino acid residues 1-38 of fibrils were exposed to the solvent, while only residues 1-18 within fibrils 91 were exposed, and no N-terminal residues within ribbons were solvent-exposed. It is likely that these differences in surface accessibility contribute to the differential binding of distinct aSYN polymorphs to partner proteins. We thus posit that the polypeptides exposed on the surface of distinct aSYN fibrillar polymorphs are comparable to fingerprints. Our findings have diagnostic and therapeutic potential, particularly in the prion-like propagation of fibrillar aSYN, as they can facilitate the design of ligands that specifically bind and distinguish between fibrillar polymorphs.
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https://hal-cea.archives-ouvertes.fr/cea-03219237
Contributor : Ronald Melki <>
Submitted on : Thursday, May 6, 2021 - 11:39:26 AM
Last modification on : Friday, May 7, 2021 - 3:22:01 AM

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Maud Landureau, Virginie Redeker, Tracy Bellande, Stéphanie Eyquem, Ronald Melki. The differential solvent exposure of N-terminal residues provides ‘fingerprints’ of alpha-synuclein fibrillar polymorphs. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2021, pp.100737. ⟨10.1016/j.jbc.2021.100737⟩. ⟨cea-03219237⟩

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