Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates
The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilament...
Gespeichert in:
Veröffentlicht in: | Journal of the American Chemical Society 2024-04, Vol.146 (15), p.10537-10549 |
---|---|
Hauptverfasser: | , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 10549 |
---|---|
container_issue | 15 |
container_start_page | 10537 |
container_title | Journal of the American Chemical Society |
container_volume | 146 |
creator | Chen, Serene W. Barritt, Joseph D. Cascella, Roberta Bigi, Alessandra Cecchi, Cristina Banchelli, Martina Gallo, Angelo Jarvis, James A. Chiti, Fabrizio Dobson, Christopher M. Fusco, Giuliana De Simone, Alfonso |
description | The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity. |
doi_str_mv | 10.1021/jacs.3c14703 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3031659310</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3031659310</sourcerecordid><originalsourceid>FETCH-LOGICAL-a362t-2af540552af51a24d2bf8f6a35c3120ef5c3fc4d8603d11c07c42eb666bc0b323</originalsourceid><addsrcrecordid>eNptkL1OwzAURi0EoqWwMaOMDKT4J3bSEVUUKlVComVgihzHEa4Su9iORLe-AuJJeBEeok-CoxZYmD5d6dzv6h4AzhEcIojR9ZILNyQCJSkkB6CPKIYxRZgdgj6EEMdpxkgPnDi3DGOCM3QMeiSjLB2NUB88z71thW-t3G4-FuZNCeXX0aOsuVdGuxe1ipSOptpL28hScS-jiSqsql1UWdNEX5_bzft8rVtRywCOjS6ldgFzp-Co4rWTZ_scgKfJ7WJ8H88e7qbjm1nMCcM-xryiCaS0S8RxUuKiyirGCRUEYSirkJVIyoxBUiIkYCoSLAvGWCFgQTAZgMtd78qa11Y6nzfKCVnXXEvTupxAghgdEQQDerVDhTXOWVnlK6sabtc5gnknM-9k5nuZAb_YN7dFeP4X_rH3d7rbWprW6vDo_13fsreBCQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3031659310</pqid></control><display><type>article</type><title>Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Chen, Serene W. ; Barritt, Joseph D. ; Cascella, Roberta ; Bigi, Alessandra ; Cecchi, Cristina ; Banchelli, Martina ; Gallo, Angelo ; Jarvis, James A. ; Chiti, Fabrizio ; Dobson, Christopher M. ; Fusco, Giuliana ; De Simone, Alfonso</creator><creatorcontrib>Chen, Serene W. ; Barritt, Joseph D. ; Cascella, Roberta ; Bigi, Alessandra ; Cecchi, Cristina ; Banchelli, Martina ; Gallo, Angelo ; Jarvis, James A. ; Chiti, Fabrizio ; Dobson, Christopher M. ; Fusco, Giuliana ; De Simone, Alfonso</creatorcontrib><description>The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity.</description><identifier>ISSN: 0002-7863</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/jacs.3c14703</identifier><identifier>PMID: 38567991</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>alpha-Synuclein - chemistry ; alpha-Synuclein - genetics ; alpha-Synuclein - toxicity ; Amyloid - chemistry ; Humans ; Neurodegenerative Diseases ; Parkinson Disease - metabolism ; Protein Conformation, beta-Strand</subject><ispartof>Journal of the American Chemical Society, 2024-04, Vol.146 (15), p.10537-10549</ispartof><rights>2024 The Authors. Published by American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a362t-2af540552af51a24d2bf8f6a35c3120ef5c3fc4d8603d11c07c42eb666bc0b323</citedby><cites>FETCH-LOGICAL-a362t-2af540552af51a24d2bf8f6a35c3120ef5c3fc4d8603d11c07c42eb666bc0b323</cites><orcidid>0000-0002-4311-5305 ; 0000-0002-3644-9809 ; 0000-0001-9856-6843 ; 0000-0002-1330-1289 ; 0000-0001-5348-0552 ; 0000-0001-8387-7737 ; 0000-0001-8789-9546 ; 0000-0001-9778-4822 ; 0000-0002-1067-6288</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jacs.3c14703$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jacs.3c14703$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38567991$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Serene W.</creatorcontrib><creatorcontrib>Barritt, Joseph D.</creatorcontrib><creatorcontrib>Cascella, Roberta</creatorcontrib><creatorcontrib>Bigi, Alessandra</creatorcontrib><creatorcontrib>Cecchi, Cristina</creatorcontrib><creatorcontrib>Banchelli, Martina</creatorcontrib><creatorcontrib>Gallo, Angelo</creatorcontrib><creatorcontrib>Jarvis, James A.</creatorcontrib><creatorcontrib>Chiti, Fabrizio</creatorcontrib><creatorcontrib>Dobson, Christopher M.</creatorcontrib><creatorcontrib>Fusco, Giuliana</creatorcontrib><creatorcontrib>De Simone, Alfonso</creatorcontrib><title>Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity.</description><subject>alpha-Synuclein - chemistry</subject><subject>alpha-Synuclein - genetics</subject><subject>alpha-Synuclein - toxicity</subject><subject>Amyloid - chemistry</subject><subject>Humans</subject><subject>Neurodegenerative Diseases</subject><subject>Parkinson Disease - metabolism</subject><subject>Protein Conformation, beta-Strand</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkL1OwzAURi0EoqWwMaOMDKT4J3bSEVUUKlVComVgihzHEa4Su9iORLe-AuJJeBEeok-CoxZYmD5d6dzv6h4AzhEcIojR9ZILNyQCJSkkB6CPKIYxRZgdgj6EEMdpxkgPnDi3DGOCM3QMeiSjLB2NUB88z71thW-t3G4-FuZNCeXX0aOsuVdGuxe1ipSOptpL28hScS-jiSqsql1UWdNEX5_bzft8rVtRywCOjS6ldgFzp-Co4rWTZ_scgKfJ7WJ8H88e7qbjm1nMCcM-xryiCaS0S8RxUuKiyirGCRUEYSirkJVIyoxBUiIkYCoSLAvGWCFgQTAZgMtd78qa11Y6nzfKCVnXXEvTupxAghgdEQQDerVDhTXOWVnlK6sabtc5gnknM-9k5nuZAb_YN7dFeP4X_rH3d7rbWprW6vDo_13fsreBCQ</recordid><startdate>20240417</startdate><enddate>20240417</enddate><creator>Chen, Serene W.</creator><creator>Barritt, Joseph D.</creator><creator>Cascella, Roberta</creator><creator>Bigi, Alessandra</creator><creator>Cecchi, Cristina</creator><creator>Banchelli, Martina</creator><creator>Gallo, Angelo</creator><creator>Jarvis, James A.</creator><creator>Chiti, Fabrizio</creator><creator>Dobson, Christopher M.</creator><creator>Fusco, Giuliana</creator><creator>De Simone, Alfonso</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4311-5305</orcidid><orcidid>https://orcid.org/0000-0002-3644-9809</orcidid><orcidid>https://orcid.org/0000-0001-9856-6843</orcidid><orcidid>https://orcid.org/0000-0002-1330-1289</orcidid><orcidid>https://orcid.org/0000-0001-5348-0552</orcidid><orcidid>https://orcid.org/0000-0001-8387-7737</orcidid><orcidid>https://orcid.org/0000-0001-8789-9546</orcidid><orcidid>https://orcid.org/0000-0001-9778-4822</orcidid><orcidid>https://orcid.org/0000-0002-1067-6288</orcidid></search><sort><creationdate>20240417</creationdate><title>Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates</title><author>Chen, Serene W. ; Barritt, Joseph D. ; Cascella, Roberta ; Bigi, Alessandra ; Cecchi, Cristina ; Banchelli, Martina ; Gallo, Angelo ; Jarvis, James A. ; Chiti, Fabrizio ; Dobson, Christopher M. ; Fusco, Giuliana ; De Simone, Alfonso</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a362t-2af540552af51a24d2bf8f6a35c3120ef5c3fc4d8603d11c07c42eb666bc0b323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>alpha-Synuclein - chemistry</topic><topic>alpha-Synuclein - genetics</topic><topic>alpha-Synuclein - toxicity</topic><topic>Amyloid - chemistry</topic><topic>Humans</topic><topic>Neurodegenerative Diseases</topic><topic>Parkinson Disease - metabolism</topic><topic>Protein Conformation, beta-Strand</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Serene W.</creatorcontrib><creatorcontrib>Barritt, Joseph D.</creatorcontrib><creatorcontrib>Cascella, Roberta</creatorcontrib><creatorcontrib>Bigi, Alessandra</creatorcontrib><creatorcontrib>Cecchi, Cristina</creatorcontrib><creatorcontrib>Banchelli, Martina</creatorcontrib><creatorcontrib>Gallo, Angelo</creatorcontrib><creatorcontrib>Jarvis, James A.</creatorcontrib><creatorcontrib>Chiti, Fabrizio</creatorcontrib><creatorcontrib>Dobson, Christopher M.</creatorcontrib><creatorcontrib>Fusco, Giuliana</creatorcontrib><creatorcontrib>De Simone, Alfonso</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of the American Chemical Society</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Serene W.</au><au>Barritt, Joseph D.</au><au>Cascella, Roberta</au><au>Bigi, Alessandra</au><au>Cecchi, Cristina</au><au>Banchelli, Martina</au><au>Gallo, Angelo</au><au>Jarvis, James A.</au><au>Chiti, Fabrizio</au><au>Dobson, Christopher M.</au><au>Fusco, Giuliana</au><au>De Simone, Alfonso</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates</atitle><jtitle>Journal of the American Chemical Society</jtitle><addtitle>J. Am. Chem. Soc</addtitle><date>2024-04-17</date><risdate>2024</risdate><volume>146</volume><issue>15</issue><spage>10537</spage><epage>10549</epage><pages>10537-10549</pages><issn>0002-7863</issn><eissn>1520-5126</eissn><abstract>The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>38567991</pmid><doi>10.1021/jacs.3c14703</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-4311-5305</orcidid><orcidid>https://orcid.org/0000-0002-3644-9809</orcidid><orcidid>https://orcid.org/0000-0001-9856-6843</orcidid><orcidid>https://orcid.org/0000-0002-1330-1289</orcidid><orcidid>https://orcid.org/0000-0001-5348-0552</orcidid><orcidid>https://orcid.org/0000-0001-8387-7737</orcidid><orcidid>https://orcid.org/0000-0001-8789-9546</orcidid><orcidid>https://orcid.org/0000-0001-9778-4822</orcidid><orcidid>https://orcid.org/0000-0002-1067-6288</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0002-7863 |
ispartof | Journal of the American Chemical Society, 2024-04, Vol.146 (15), p.10537-10549 |
issn | 0002-7863 1520-5126 |
language | eng |
recordid | cdi_proquest_miscellaneous_3031659310 |
source | MEDLINE; American Chemical Society Journals |
subjects | alpha-Synuclein - chemistry alpha-Synuclein - genetics alpha-Synuclein - toxicity Amyloid - chemistry Humans Neurodegenerative Diseases Parkinson Disease - metabolism Protein Conformation, beta-Strand |
title | Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T06%3A09%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structure%E2%80%93Toxicity%20Relationship%20in%20Intermediate%20Fibrils%20from%20%CE%B1%E2%80%91Synuclein%20Condensates&rft.jtitle=Journal%20of%20the%20American%20Chemical%20Society&rft.au=Chen,%20Serene%20W.&rft.date=2024-04-17&rft.volume=146&rft.issue=15&rft.spage=10537&rft.epage=10549&rft.pages=10537-10549&rft.issn=0002-7863&rft.eissn=1520-5126&rft_id=info:doi/10.1021/jacs.3c14703&rft_dat=%3Cproquest_cross%3E3031659310%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3031659310&rft_id=info:pmid/38567991&rfr_iscdi=true |