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 C-terminal region spanning residues 94 to 140 exhibited similarly high solvent accessibility in these three polymorphs. However, the N-terminal amino acid residues 1 to 38 of fibrils were exposed to the solvent, while only residues 1 to 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. 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 C-terminal region spanning residues 94 to 140 exhibited similarly high solvent accessibility in these three polymorphs. However, the N-terminal amino acid residues 1 to 38 of fibrils were exposed to the solvent, while only residues 1 to 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. Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) are characterized by the presence of aSYN-rich deposits within the central and peripheral nervous systems (1Spillantini M.G. Crowther R.A. Jakes R. Hasegawa M. Goedert M. 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M. protein structure by limited PubMed Google Scholar, L. E. A. Conformational properties of the of alpha-synuclein by limited of the C-terminal 2006; PubMed Scopus Google by with and to from fibrillar polymorphs exposed to the We by solvent accessibility the amino acid by hydrogen–deuterium with of by A protein structure Sci. 2: PubMed Google Scholar, E. hydrogen–deuterium the aggregation of the Parkinson’s Chem. Neurosci. PubMed Scopus Google Scholar). We that aSYN C-terminal amino acid stretch 94 to 140 is to the solvent in three fibrillar polymorphs. with the differential of aSYN N-terminal while aSYN amino acid stretch 1 to 38 is exposed to the solvent in the fibrils, it is in ribbons and in in the fibrils The differences we differences in Our findings the to design ligands with diagnostic and therapeutic that distinct aSYN and are of aSYN We used to human aSYN into the three distinct fibrillar fibrils, ribbons, and fibrils The fibrils were L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google ribbons were in a with a and fibrils 91 were in a with a high as previously L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar, J. Bousset L. L. Melki R. A. of the of α-synuclein fibrils: of a PubMed Scopus Google Scholar, A. Bousset L. J. Melki R. properties of distinct fibrillar polymorphs of the protein PubMed Scopus Google Scholar). The and of the fibrillar polymorphs were by and fibrils 91 a with while ribbons L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar, A. Bousset L. J. Melki R. properties of distinct fibrillar polymorphs of the protein PubMed Scopus Google Scholar). We the three fibrillar polymorphs to limited and to their and can and within aSYN, These two a of the we within amino acid exposed to the solvent the surface of the polymorphs. and comparable to were and with and where aSYN is within to into polypeptides with These that structurally distinct fibrillar aSYN polymorphs to the solvent fibrillar upon by the polypeptides were in the and fibrils, ribbons, and fibrils 91 were to that aSYN polypeptides within the fibrillar that only fibrils their amyloid We the accessibility of spanning aSYN structure to in aSYN fibrils, ribbons, and fibrils The were on that were exposed to aSYN amino acid stretch 1 to 91 to and to ribbons, which that its is involved in amyloid in with we previously L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar, J. Bousset L. L. Melki R. A. of the of α-synuclein fibrils: of a PubMed Scopus Google Scholar, J. B. Bousset L. Melki R. A. of PubMed Scopus Google Scholar, J. Bousset L. B. Melki R. A. of two α-synuclein PubMed Scopus Google Scholar). The antibody fibrillar that aSYN C-terminal is exposed to the solvent, in with L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar, J. Bousset L. L. Melki R. A. of the of α-synuclein fibrils: of a PubMed Scopus Google Scholar, J. B. Bousset L. Melki R. A. of PubMed Scopus Google Scholar, J. Bousset L. B. Melki R. A. of two α-synuclein PubMed Scopus Google Scholar). binds fibrillar aSYN polymorphs better its which a aSYN C-terminal domain or a binding to a aSYN C-terminal domain in fibrillar polymorphs. to bind with the or of aSYN amino acid stretch 91 to within the amyloid core of the fibrillar polymorphs we L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar, J. Bousset L. L. Melki R. A. of the of α-synuclein fibrils: of a PubMed Scopus Google Scholar, J. B. Bousset L. Melki R. A. of PubMed Scopus Google Scholar, J. 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PubMed Scopus Google and aSYN amino acid 1 to to to 91 to and to the and with that the amino acid stretch 91 to is in and 1 and The presence or of and within the polypeptides and with the The antibody polypeptides from of the ribbons the polymorphs fibrils and fibrils 91 as by the of and We from that the amino acid stretch 1 to is to in the ribbons while it is in the polymorphs fibrils and fibrils The and polypeptides by and by We from that the amino acid stretch to is to in aSYN fibrillar polymorphs. polypeptides antibody binding which the amino acid stretch to is to the and the polypeptides are The binding of and to aSYN fibrillar polymorphs fibrils, fibrils 91, and ribbons is in with the with It that the amino acid stretch 1 to is to in aSYN ribbons while it is in the polymorphs fibrils and fibrils 91 that the amino acid stretch to is to in aSYN fibrillar polymorphs and that the amino acid stretch to is to the in aSYN fibrillar polymorphs. we aSYN fibrillar polymorphs and by We used in the with a acid the of the polypeptides The of the polypeptides by and are in in to aSYN and C-terminal accessibility we by and their are in and The we aSYN is as a their to the These that the C-terminal stretch to 140 is to in fibrillar aSYN Our also that the aSYN N-terminal stretch 1 to 18 is in the polymorphs ribbons while it is in fibrils and fibrils 91, and the 1 to is only in the fibrils. polypeptides from limited of fibrillar aSYN polymorphs by and were by as and in and abundant C-terminal to the the to 140 and and to 140 and abundant N-terminal polypeptides were and N-terminal to in the The differential to the solvent of aSYN within the fibrillar polymorphs fibrils, ribbons, and fibrils 91 from the we is in that aSYN C-terminal is exposed in a to the solvent and to in the three structurally distinct fibrillar polymorphs. with the N-terminal that exposed to in the polymorphs fibrils and fibrils 91 in we hydrogen–deuterium to the of with the from the protein with the of secondary structure is a of in as an amyloid core of by A protein structure Sci. 2: PubMed Google Scholar). We the that and of aSYN fibrillar polymorphs and aSYN with We on by of of the fibrillar polymorphs by of a of and aSYN and fibrillar The of the and with by of and The ions used were with a as they are better and abundant as We that the with or abundant were from aSYN and fibrillar polymorphs and in a Monomeric aSYN exhibited to in were on assembled aSYN fibrillar polymorphs that from aSYN can used as within spectrum involved in and from the solvent within an aSYN fibrillar of The the within the fibrillar while the from the from aSYN, as previously E. hydrogen–deuterium the aggregation of the Parkinson’s Chem. Neurosci. PubMed Scopus Google Scholar). In that are or exposed the of aSYN fibrillar polymorphs of they in aSYN and fibrillar polymorphs. The within of the we The from aSYN fibrillar polymorphs exhibited from 1 to in polypeptides that within were three aSYN fibrillar polymorphs. The to an to that of the in We the of an of within of fibrils in the of and the the of is In 95 to exposed to the solvent in and fibrillar aSYN polymorphs the we that aSYN amino acid stretch 95 to 140 is exposed to the solvent within fibrillar polymorphs. with aSYN N-terminal that exposed residues 38 or in the polymorphs fibrils and fibrils 91, in the These findings are in with the differential accessibility and limited The an of the core of aSYN fibrillar polymorphs assembled in or from the of and to have been T. Fernandez C.O. D. S. M. W.S. M. of α-synuclein fibrils from 2019; PubMed Scopus Google Scholar, A. G. A. Bousset L. F. C. S. Melki R. V. The differences between α-synuclein of Parkinson’s multiple system atrophy and dementia with Lewy PubMed Scopus Google Scholar, R. P. D. P. M. A. J. R. Melki R. A. Bousset L. et of human alpha-synuclein fibrils by 2019; PubMed Scopus (61) Google Scholar, C. F. Zhang D. C. structure of α-synuclein by PubMed Scopus Google Scholar, B. P. P. 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A. α-Synuclein assemblies neuronal and J. 2015; PubMed Scopus Google Scholar). a of that can an differential accessibility of limited and we have mapped the of distinct aSYN fibrillar polymorphs. We that aSYN C-terminal amino acid stretch spanning 94 to 140 within three aSYN polymorphs we is exposed to the is with the we that aSYN C-terminal is flexible within fibrillar polymorphs J. Bousset L. L. Melki R. A. of the of α-synuclein fibrils: of a PubMed Scopus Google Scholar, J. B. Bousset L. Melki R. A. of PubMed Scopus Google Scholar, J. Bousset L. B. Melki R. A. of two α-synuclein PubMed Scopus Google Scholar). Our are also with the two of aSYN fibrils by that the amino acid residues stretch 95 to 140 is and thus R. P. D. P. M. A. J. R. Melki R. A. Bousset L. et of human alpha-synuclein fibrils by 2019; PubMed Scopus (61) Google Scholar). The by as exposed to the solvent within aSYN fibrils are that by limited is to the that binding to protein Our limited that and fibrillar polymorphs residues or and the C-terminal and were into suggests that the distinguish a of within aSYN C-terminal domain in the fibrils as a in suggests that aSYN amino acid stretch to 140 a secondary structure with aSYN C-terminal may with the amino acid stretch on from the partner within the two of aSYN fibrils we by R. P. D. P. M. A. J. R. Melki R. A. Bousset L. et of human alpha-synuclein fibrils by 2019; PubMed Scopus (61) Google and has been to a in within the fibrillar form of the protein D. S. of of α-synuclein in the assembly of PubMed Scopus Google Scholar, Jiang C. The of the of human between the and Lett. PubMed Scopus Google Scholar). aSYN fibrillar polymorphs of fibrillar as by suggests that the and interactions within the fibrillar polymorphs the aSYN polymorphs a to proteolysis, in a to fibrils assembled from aSYN L. C. Zhang S. L. C-terminal the aggregation and of A in Parkinson’s Mol. Dis. PubMed Scopus Google Scholar, C. C-terminal of promotes amyloid Sci. PubMed Google Scholar, J. C. B. of α-synuclein in and of amyloid Chem. Neurosci. PubMed Scopus Google Scholar). is to the of the negatively C-terminal residues that the fibrils from We differences in aSYN N-terminal to the solvent in distinct fibrillar polymorphs. aSYN N-terminal to and also in in ribbons it exposed to the solvent amino acid 38 or in the polymorphs fibrils and fibrils 91, These findings are with we previously J. Bousset L. L. Melki R. A. of the of α-synuclein fibrils: of a PubMed Scopus Google Scholar, J. B. Bousset L. Melki R. A. of PubMed Scopus Google Scholar, J. Bousset L. B. Melki R. A. of two α-synuclein PubMed Scopus Google and the of the we to within amyloid fibrils. the amino acid we identify as to or are within we previously showed to adopt a spanning residues to and to 38 in aSYN fibrils. in these amino acid the surface of the fibrils on the we R. P. D. P. M. A. J. R. Melki R. A. Bousset L. et of human alpha-synuclein fibrils by 2019; PubMed Scopus (61) Google in of an amyloid core where is of the of aSYN fibrillar polymorphs to the they with and and in the of their We differences and between distinct fibrillar aSYN polymorphs. The that aSYN stretch spanning residues 95 to 140 is to to and exposed to the solvent in fibrillar polymorphs suggests that region a fibrillar from It also suggests that the of region is in structurally distinct aSYN fibrillar polymorphs. is in with we aSYN N-terminal the accessibility to to and to the solvent of the stretch spanning residues 1 to 38 distinct aSYN fibrillar polymorphs. The differential of aSYN N-terminal stretch to the solvent within fibrillar assemblies suggests they have and as a distinct pathogenic properties and neuronal that ligands of the C-terminal of aSYN diagnostic synucleinopathies while ligands of aSYN N-terminal from In ligands may therapeutic as they with and may the between pathogenic assemblies and to of pathogenic aSYN assemblies from patients’ the we and of the and to a better of synucleinopathies and the design of to with their prion-like aSYN and assembly into the fibrillar polymorphs fibrils, ribbons, and fibrils 91 were as previously L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar, A. Bousset L. J. Melki R. properties of distinct fibrillar polymorphs of the protein PubMed Scopus Google Scholar, Bousset L. M. V. J. A. Melki R. binding and of distinct α-synuclein fibrillar J. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Melki R. J. the of the with alpha-synuclein J. PubMed Scopus Google Scholar). as previously L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar). Monomeric alpha-synuclein the used limited and accessibility were assemblies by the of aSYN in the from the protein The of aSYN fibrillar polymorphs as previously L. L. G. J. P. B. V. A. Melki R. and of two alpha-synuclein 2013; PubMed Scopus Google Scholar). Monomeric or fibrillar aSYN in with or in with were of the and 60 and into with or or where and by of of the were in and to or and and to were to The were with 1 with the or and The were with with and 1 with a to and a The were 1 to a with the antibody fibrillar aSYN polymorphs were in on a The with 1 and with as of the we we a and the aSYN and We by multiple and the aSYN to the aSYN, used as to a and to differences are The of aSYN and fibrillar polymorphs were in as and the of from to or the of from to in acid were to acid or as and were as in and acid The were on a were in or and aSYN or a of 1 to and from in and aSYN in the used Identification of the the and a between and in and in were of The we used from et V. F. Bousset L. Melki R. of the assembly of the into protein Mol. Biol. PubMed Scopus Google Scholar). aSYN and fibrillar polymorphs were in to by of the protein into 38 of of an in were or The by the and the by of of an of acid in The were by of of an to protein The were in the of an and the were in the by a The were a as previously V. F. Bousset L. Melki R. of the assembly of the into protein Mol. Biol. PubMed Scopus Google the a and on a The were in the and in the to the of 95 to characterized by as shown in between and were the of with have a better we their by on the and by We by with a as previously M. V. E. Bousset L. T. Melki R. Interaction of the and with fibrillar on by and of PubMed Scopus Google Scholar). were a with the the aSYN and We of The of to as previously V. F. Bousset L. Melki R. of the assembly of the into protein Mol. Biol. 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