Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ
| Autor(a) principal: | |
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| Data de Publicação: | 2020 |
| 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/10451/47271 |
Resumo: | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
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Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of AβAβAlzheimer’s diseaseAPP C-terminal fragmentsAutophagySEPTIN5© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Alzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.This research was supported by the Academy of Finland (grant numbers 307866 and 315459), the Sigrid Jusélius Foundation, the Strategic Neuroscience Funding of the University of Eastern Finland, and the National Institute of Mental Health of the National Institutes of Health (grant numbers R01MH099660, R01DC015776, R21HD053114, and U54HD090260). Catarina B. Ferreira is a PhD Fellow (NeurULisboa - Integrated Neurosciences PhD program, supported by an individual grant from Fundação para a Ciência e Tecnologia (FCT), (PD/BD/128390/2017, SFRH/PD/BD/114441/2016, PD/BD/128091/2016). Work was also supported by Santa Casa da Misericórdia de Lisboa (MB37-2017) and SynaNet (LISBOA-01-0145-FEDER-0073919), under the grant agreement no. 692340, and the project was co-financed by FEDER, POR Lisboa 2020, Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia.MDPIRepositório da Universidade de LisboaMarttinen, MikaelFerreira, Catarina B.Paldanius, Kaisa M. A.Takalo, MariNatunen, TeemuMäkinen, PetraLeppänen, LuukasLeinonen, VilleTanigaki, KenjiKang, GinaHiroi, NoboruSoininen, HilkkaRilla, KirsiHaapasalo, AnnakaisaHiltunen, Mikko2021-04-07T11:28:06Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/47271engCells. 2020 Nov 15;9(11):248210.3390/cells91124822073-4409info: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:RCAAP2023-11-08T16:50:05Zoai:repositorio.ul.pt:10451/47271Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:21.248168Repositório 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 |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| title |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| spellingShingle |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ Marttinen, Mikael Aβ Alzheimer’s disease APP C-terminal fragments Autophagy SEPTIN5 |
| title_short |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| title_full |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| title_fullStr |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| title_full_unstemmed |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| title_sort |
Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ |
| author |
Marttinen, Mikael |
| author_facet |
Marttinen, Mikael Ferreira, Catarina B. Paldanius, Kaisa M. A. Takalo, Mari Natunen, Teemu Mäkinen, Petra Leppänen, Luukas Leinonen, Ville Tanigaki, Kenji Kang, Gina Hiroi, Noboru Soininen, Hilkka Rilla, Kirsi Haapasalo, Annakaisa Hiltunen, Mikko |
| author_role |
author |
| author2 |
Ferreira, Catarina B. Paldanius, Kaisa M. A. Takalo, Mari Natunen, Teemu Mäkinen, Petra Leppänen, Luukas Leinonen, Ville Tanigaki, Kenji Kang, Gina Hiroi, Noboru Soininen, Hilkka Rilla, Kirsi Haapasalo, Annakaisa Hiltunen, Mikko |
| author2_role |
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 |
Marttinen, Mikael Ferreira, Catarina B. Paldanius, Kaisa M. A. Takalo, Mari Natunen, Teemu Mäkinen, Petra Leppänen, Luukas Leinonen, Ville Tanigaki, Kenji Kang, Gina Hiroi, Noboru Soininen, Hilkka Rilla, Kirsi Haapasalo, Annakaisa Hiltunen, Mikko |
| dc.subject.por.fl_str_mv |
Aβ Alzheimer’s disease APP C-terminal fragments Autophagy SEPTIN5 |
| topic |
Aβ Alzheimer’s disease APP C-terminal fragments Autophagy SEPTIN5 |
| description |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-04-07T11:28:06Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/47271 |
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http://hdl.handle.net/10451/47271 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
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Cells. 2020 Nov 15;9(11):2482 10.3390/cells9112482 2073-4409 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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MDPI |
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MDPI |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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