Systematic comparison of the effects of Alpha-synuclein mutations on its oligomerization and aggregation
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , , , , , , , , , , |
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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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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7160 |
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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 |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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 |
repository.mail.fl_str_mv |
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1799134576065380352 |