Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation

Detalhes bibliográficos
Autor(a) principal: Lázaro, Diana F.
Data de Publicação: 2014
Outros Autores: Rodrigues, Eva F., Langohr, Ramona, Shahpasandzadeh, Hedieh, Ribeiro, Thales, Guerreiro, Patrícia, Gerhardt, Ellen, Kröhnert, Katharina, Klucken, Jochen, Pereira, Marcos D., Popova, Blagovesta, Kruse, Niels, Mollenhauer, Brit, Rizzoli, Silvio O., Braus, Gerhard H., Danzer, Karin M., Outeiro, Tiago
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/51318
Resumo: Copyright: © 2014 Lázaro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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spelling Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregationCopyright: © 2014 Lázaro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.This work was supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB).PLOSRepositório da Universidade de LisboaLázaro, Diana F.Rodrigues, Eva F.Langohr, RamonaShahpasandzadeh, HediehRibeiro, ThalesGuerreiro, PatríciaGerhardt, EllenKröhnert, KatharinaKlucken, JochenPereira, Marcos D.Popova, BlagovestaKruse, NielsMollenhauer, BritRizzoli, Silvio O.Braus, Gerhard H.Danzer, Karin M.Outeiro, Tiago2022-02-15T15:02:31Z20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/51318engPLoS Genet 10(11): e1004741.1553-739010.1371/journal.pgen.10047411553-7404info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:55:55Zoai:repositorio.ul.pt:10451/51318Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:02:37.017298Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
title Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
spellingShingle Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
Lázaro, Diana F.
title_short Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
title_full Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
title_fullStr Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
title_full_unstemmed Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
title_sort Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
author Lázaro, Diana F.
author_facet Lázaro, Diana F.
Rodrigues, Eva F.
Langohr, Ramona
Shahpasandzadeh, Hedieh
Ribeiro, Thales
Guerreiro, Patrícia
Gerhardt, Ellen
Kröhnert, Katharina
Klucken, Jochen
Pereira, Marcos D.
Popova, Blagovesta
Kruse, Niels
Mollenhauer, Brit
Rizzoli, Silvio O.
Braus, Gerhard H.
Danzer, Karin M.
Outeiro, Tiago
author_role author
author2 Rodrigues, Eva F.
Langohr, Ramona
Shahpasandzadeh, Hedieh
Ribeiro, Thales
Guerreiro, Patrícia
Gerhardt, Ellen
Kröhnert, Katharina
Klucken, Jochen
Pereira, Marcos D.
Popova, Blagovesta
Kruse, Niels
Mollenhauer, Brit
Rizzoli, Silvio O.
Braus, Gerhard H.
Danzer, Karin M.
Outeiro, Tiago
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Lázaro, Diana F.
Rodrigues, Eva F.
Langohr, Ramona
Shahpasandzadeh, Hedieh
Ribeiro, Thales
Guerreiro, Patrícia
Gerhardt, Ellen
Kröhnert, Katharina
Klucken, Jochen
Pereira, Marcos D.
Popova, Blagovesta
Kruse, Niels
Mollenhauer, Brit
Rizzoli, Silvio O.
Braus, Gerhard H.
Danzer, Karin M.
Outeiro, Tiago
description Copyright: © 2014 Lázaro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
publishDate 2014
dc.date.none.fl_str_mv 2014
2014-01-01T00:00:00Z
2022-02-15T15:02:31Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/51318
url http://hdl.handle.net/10451/51318
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv PLoS Genet 10(11): e1004741.
1553-7390
10.1371/journal.pgen.1004741
1553-7404
dc.rights.driver.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 PLOS
publisher.none.fl_str_mv PLOS
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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