Cathepsin D
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2022 |
| 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/10362/145740 |
Resumo: | Funding Information: This work was supported in part by the Deutsche Forschungsgemeinschaft ( SFB877 , A3 and Z2) and the Canadian Institutes of Health Research – CIHR (to GM). Publisher Copyright: © 2022 |
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Cathepsin DAnalysis of its potential role as an amyloid beta degrading proteaseAlzheimer's diseaseAmyloid betaAmyloid precursor proteinCathepsin-DLysosomeNeuronal ceroid lipofuscinosis 10ProteolysisNeurologySDG 3 - Good Health and Well-beingFunding Information: This work was supported in part by the Deutsche Forschungsgemeinschaft ( SFB877 , A3 and Z2) and the Canadian Institutes of Health Research – CIHR (to GM). Publisher Copyright: © 2022Proteolysis catalyzed by the major lysosomal aspartyl protease cathepsin-D (CTSD) appears to be of pivotal importance for proteostasis within the central nervous system and in neurodegeneration. Neuronal Ceroid Lipofuscinosis (NCL) type 10 is caused by a lack of CTSD leading to a defective autophagic flow and pathological accumulation of proteins. We previously demonstrated a therapeutic-relevant clearance of protein aggregates after dosing a NCL10 mouse model with recombinant human pro-cathepsin-D (proCTSD). Similar results could be achieved in cells and mice accumulating α-synuclein. Prompted by these positive effects and our in vitro findings showing that cathepsin-D can cleave the Alzheimer's Disease (AD)-causing amyloid beta peptides (Aβ), we envisaged that such a treatment with proCTSD could similarly be effective in clearance of potentially toxic Aβ species. We demonstrated that CTSD is able to cleave human Aβ1–42 by using liquid chromatography-mass spectrometry. Intracerebral dosing of proCTSD in a NCL10 (CTSD knockout) mouse model revealed uptake and processing of CTSD to its mature and active form. However, the re-addition of CTSD did not obviously affect intracellular APP processing or the generation of soluble APP and Aβ-species. ProCTSD treated HEK cells in comparison with untreated cells were found to contain comparable levels of soluble and membrane bound APP and Aβ-species. Also, the early intracranial application (P1 and P20) of proCTSD in the 5xFAD mouse model did not change Aβ pathology, plaque number and plaque composition and neuroinflammation, however we observed an increased level of Aβ1–42 in the CSF. Our data confirm proteolytic cleavage of human Aβ1–42 by CTSD but exclude a prominent role of CTSD in APP processing and Aβ degradation in our in vitro and in vivo models.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)iNOVA4Health - pólo NMSRUNGallwitz, LisaSchmidt, LinaMarques, André R.A.Tholey, AndreasCassidy, LiamUlku, IremMulthaup, GerhardDi Spiezio, AlessandroSaftig, Paul2022-11-23T22:26:58Z2022-122022-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/145740eng0969-9961PURE: 47854946https://doi.org/10.1016/j.nbd.2022.105919info: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:RCAAP2024-03-11T05:26:21Zoai:run.unl.pt:10362/145740Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:52:14.321599Repositório 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 |
Cathepsin D Analysis of its potential role as an amyloid beta degrading protease |
| title |
Cathepsin D |
| spellingShingle |
Cathepsin D Gallwitz, Lisa Alzheimer's disease Amyloid beta Amyloid precursor protein Cathepsin-D Lysosome Neuronal ceroid lipofuscinosis 10 Proteolysis Neurology SDG 3 - Good Health and Well-being |
| title_short |
Cathepsin D |
| title_full |
Cathepsin D |
| title_fullStr |
Cathepsin D |
| title_full_unstemmed |
Cathepsin D |
| title_sort |
Cathepsin D |
| author |
Gallwitz, Lisa |
| author_facet |
Gallwitz, Lisa Schmidt, Lina Marques, André R.A. Tholey, Andreas Cassidy, Liam Ulku, Irem Multhaup, Gerhard Di Spiezio, Alessandro Saftig, Paul |
| author_role |
author |
| author2 |
Schmidt, Lina Marques, André R.A. Tholey, Andreas Cassidy, Liam Ulku, Irem Multhaup, Gerhard Di Spiezio, Alessandro Saftig, Paul |
| author2_role |
author author author author author author author author |
| dc.contributor.none.fl_str_mv |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) iNOVA4Health - pólo NMS RUN |
| dc.contributor.author.fl_str_mv |
Gallwitz, Lisa Schmidt, Lina Marques, André R.A. Tholey, Andreas Cassidy, Liam Ulku, Irem Multhaup, Gerhard Di Spiezio, Alessandro Saftig, Paul |
| dc.subject.por.fl_str_mv |
Alzheimer's disease Amyloid beta Amyloid precursor protein Cathepsin-D Lysosome Neuronal ceroid lipofuscinosis 10 Proteolysis Neurology SDG 3 - Good Health and Well-being |
| topic |
Alzheimer's disease Amyloid beta Amyloid precursor protein Cathepsin-D Lysosome Neuronal ceroid lipofuscinosis 10 Proteolysis Neurology SDG 3 - Good Health and Well-being |
| description |
Funding Information: This work was supported in part by the Deutsche Forschungsgemeinschaft ( SFB877 , A3 and Z2) and the Canadian Institutes of Health Research – CIHR (to GM). Publisher Copyright: © 2022 |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022-11-23T22:26:58Z 2022-12 2022-12-01T00:00:00Z |
| 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/10362/145740 |
| url |
http://hdl.handle.net/10362/145740 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
0969-9961 PURE: 47854946 https://doi.org/10.1016/j.nbd.2022.105919 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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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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