FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade

Morphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecula...

ver descrição completa

Detalhes bibliográficos
Autores: De Rossi, Pierre, Lewis, Amanda J., Furrer, Johanna, De Vos, Laura, Demeter, Tomas, Zbinden, Aurélie, Zhong, Weijia, Wiersma, Vera I., Scialo, Carlo, Weber, Julien, Guo, Zhongning, Scaramuzza, Stefano, Di Fabrizio, Marta, Böing, Carolin, Castaño-Díez, Daniel, Al-Amoudi, Ashraf, Pérez Berlanga, Manuela, Lashley, Tammaryn, Stahlberg, Henning, Polymenidou, Magdalini
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/404642
Acesso em linha:http://hdl.handle.net/10261/404642
https://api.elsevier.com/content/abstract/scopus_id/85119609555
Access Level:acceso abierto
Palavra-chave:FTLD-TDP
TDP-43
TDP-43 strains
Frontotemporal dementia
Prion-like
id ES_03e60f9bbc90ee83e88aaf1080c2cbdd
oai_identifier_str oai:digital.csic.es:10261/404642
network_acronym_str ES
network_name_str España
repository_id_str
spelling FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascadeDe Rossi, PierreLewis, Amanda J.Furrer, JohannaDe Vos, LauraDemeter, TomasZbinden, AurélieZhong, WeijiaWiersma, Vera I.Scialo, CarloWeber, JulienGuo, ZhongningScaramuzza, StefanoDi Fabrizio, MartaBöing, CarolinCastaño-Díez, DanielAl-Amoudi, AshrafPérez Berlanga, ManuelaLashley, TammarynStahlberg, HenningPolymenidou, MagdaliniFTLD-TDPTDP-43TDP-43 strainsFrontotemporal dementiaPrion-likeMorphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD-TDP-A and FTLD-TDP-C aggregates. Upon inoculation of patient-derived aggregates in cells, FTLD-TDP-A seeds amplify in a template-dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD-TDP-C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N-to-C directionality and with subtype-specific timelines. The resulting FTLD-TDP-A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD-TDP-C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics.This study was supported by the Swiss National Science Foundation (Project Grant 310030_192650) and by the Association for Frontotemporal Dementia (FTD Biomarkers Initiative Grant) to MP. PDR and AJL were supported by the Stiftung Synapsis Alzheimer Forschung Schweiz (Career Development Awards; No. 2019‐CDA01 and 2020‐CDA02) VIW was supported by the FEBS Long‐Term Fellowship. DC‐D and SS were supported by the Human Frontiers Science Program (grant RGP0017/2020) and the Swiss National Science Foundation (Project Grant 205321_179041). Open access funding provided by Universitat Zurich.Peer reviewedEMBO PressSwiss National Science FoundationAssociation for Frontotemporal Degeneration (US)Dementia Research SwitzerlandFederation of European Biochemical SocietiesHuman Frontiers Science ProgramUniversity of ZurichDe Rossi, Pierre [0000-0002-2356-4269]Lewis, Amanda J. [0000-0001-7257-5848]Furrer, Johanna [0000-0002-3090-0013]De Vos, Laura [0000-0001-6675-6968]Demeter, Tomas [0000-0002-8761-2637]Zbinden, Aurélie [0000-0002-7785-2741]Zhong, Weijia [0000-0003-3429-250X]Wiersma, Vera I. [0000-0001-8223-4588]Scialo, Carlo [0000-0003-2393-4546]Di Fabrizio, Marta [0000-0003-3812-5995]Böing, Carolin [0000-0002-6909-9067]Al-Amoudi, Ashraf [0000-0002-3349-1948]Pérez Berlanga, Manuela [0000-0001-9064-9724]Lashley, Tammaryn [0000-0001-7389-0348]Stahlberg, Henning [0000-0002-1185-4592]Polymenidou, Magdalini [0000-0003-1271-9445]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/404642https://api.elsevier.com/content/abstract/scopus_id/85119609555reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.15252/embr.202153877https://doi.org/10.15252/embr.202153877Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4046422026-05-22T06:33:51Z
dc.title.none.fl_str_mv FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
title FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
spellingShingle FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
De Rossi, Pierre
FTLD-TDP
TDP-43
TDP-43 strains
Frontotemporal dementia
Prion-like
title_short FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
title_full FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
title_fullStr FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
title_full_unstemmed FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
title_sort FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
dc.creator.none.fl_str_mv De Rossi, Pierre
Lewis, Amanda J.
Furrer, Johanna
De Vos, Laura
Demeter, Tomas
Zbinden, Aurélie
Zhong, Weijia
Wiersma, Vera I.
Scialo, Carlo
Weber, Julien
Guo, Zhongning
Scaramuzza, Stefano
Di Fabrizio, Marta
Böing, Carolin
Castaño-Díez, Daniel
Al-Amoudi, Ashraf
Pérez Berlanga, Manuela
Lashley, Tammaryn
Stahlberg, Henning
Polymenidou, Magdalini
author De Rossi, Pierre
author_facet De Rossi, Pierre
Lewis, Amanda J.
Furrer, Johanna
De Vos, Laura
Demeter, Tomas
Zbinden, Aurélie
Zhong, Weijia
Wiersma, Vera I.
Scialo, Carlo
Weber, Julien
Guo, Zhongning
Scaramuzza, Stefano
Di Fabrizio, Marta
Böing, Carolin
Castaño-Díez, Daniel
Al-Amoudi, Ashraf
Pérez Berlanga, Manuela
Lashley, Tammaryn
Stahlberg, Henning
Polymenidou, Magdalini
author_role author
author2 Lewis, Amanda J.
Furrer, Johanna
De Vos, Laura
Demeter, Tomas
Zbinden, Aurélie
Zhong, Weijia
Wiersma, Vera I.
Scialo, Carlo
Weber, Julien
Guo, Zhongning
Scaramuzza, Stefano
Di Fabrizio, Marta
Böing, Carolin
Castaño-Díez, Daniel
Al-Amoudi, Ashraf
Pérez Berlanga, Manuela
Lashley, Tammaryn
Stahlberg, Henning
Polymenidou, Magdalini
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Swiss National Science Foundation
Association for Frontotemporal Degeneration (US)
Dementia Research Switzerland
Federation of European Biochemical Societies
Human Frontiers Science Program
University of Zurich
De Rossi, Pierre [0000-0002-2356-4269]
Lewis, Amanda J. [0000-0001-7257-5848]
Furrer, Johanna [0000-0002-3090-0013]
De Vos, Laura [0000-0001-6675-6968]
Demeter, Tomas [0000-0002-8761-2637]
Zbinden, Aurélie [0000-0002-7785-2741]
Zhong, Weijia [0000-0003-3429-250X]
Wiersma, Vera I. [0000-0001-8223-4588]
Scialo, Carlo [0000-0003-2393-4546]
Di Fabrizio, Marta [0000-0003-3812-5995]
Böing, Carolin [0000-0002-6909-9067]
Al-Amoudi, Ashraf [0000-0002-3349-1948]
Pérez Berlanga, Manuela [0000-0001-9064-9724]
Lashley, Tammaryn [0000-0001-7389-0348]
Stahlberg, Henning [0000-0002-1185-4592]
Polymenidou, Magdalini [0000-0003-1271-9445]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv FTLD-TDP
TDP-43
TDP-43 strains
Frontotemporal dementia
Prion-like
topic FTLD-TDP
TDP-43
TDP-43 strains
Frontotemporal dementia
Prion-like
description Morphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD-TDP-A and FTLD-TDP-C aggregates. Upon inoculation of patient-derived aggregates in cells, FTLD-TDP-A seeds amplify in a template-dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD-TDP-C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N-to-C directionality and with subtype-specific timelines. The resulting FTLD-TDP-A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD-TDP-C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics.
publishDate 2021
dc.date.none.fl_str_mv 2021
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/404642
https://api.elsevier.com/content/abstract/scopus_id/85119609555
url http://hdl.handle.net/10261/404642
https://api.elsevier.com/content/abstract/scopus_id/85119609555
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.15252/embr.202153877
https://doi.org/10.15252/embr.202153877
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv EMBO Press
publisher.none.fl_str_mv EMBO Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869402757851512832
score 15,811543

Registos relacionados