Investigations of S100 proteins and their role in huntingtin aggregation

Detalhes bibliográficos
Autor(a) principal: Botelho, Marta Sofia Silva da Cruz
Data de Publicação: 2023
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/62657
Resumo: Tese de mestrado, Bioquímica e Biomedicina , 2023, Universidade de Lisboa, Faculdade de Ciências
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spelling Investigations of S100 proteins and their role in huntingtin aggregationDoença de Huntingtonhuntingtinaagregação proteicaS100BTeses de mestrado - 2023Departamento de Química e BioquímicaTese de mestrado, Bioquímica e Biomedicina , 2023, Universidade de Lisboa, Faculdade de CiênciasHuntington's disease (HD) is a progressive neurodegenerative disorder characterized by an autosomal dominant inheritance, leading to a triad of motor, cognitive, and behavioural symptoms. HD is an incurable disease caused by a CAG trinucleotide repeat expansion in the HTT gene, which translates into an expanded polyglutamine tract (polyQ) in the huntingtin (Htt) protein, leading to the formation of mutant huntingtin (mHtt). The expanded polyQ tract destabilizes the conformation of huntingtin, and promotes the assembly of amyloidogenic protein aggregates, primarily composed of N-terminal Htt fragments. This accumulation disrupts various essential brain functions, ultimately leading to neuronal degeneration. S100B is a calcium-binding alarmin that is predominantly synthesized by astrocytes in the nervous system. Depending on the concentration, S100B operates as an aggravating proinflammatory cytokine or as a protective anti-aggregation chaperone, inhibiting amyloid aggregation and mitigating toxicity in the presence of Ca2+ . Considering S100B's significance in other neurodegenerative conditions and its chaperone role, this work aims to explore its potential involvement in huntingtin aggregation and in HD pathology. To address this, both cellular assays and in vitro assays were performed. First, interactions between S100B and huntingtin were investigated using a dual luminescence-based co-immunoprecipitation assay (LuTHy), for detection of protein-protein interactions in mammalian cells. Secondly, the effects of endogenous and exogenous S100B on live cells expressing wild-type and mutant huntingtin were studied through bimolecular fluorescence complementation (BiFC) assays, to evaluate potential changes in the amounts and dynamics of Htt inclusions. Furthermore, in vitro assays explored how the S100B protein influences Htt aggregation, employing a FRET-based Htt aggregate seeding (FRASE) approach, which revealed that S100B significantly delays and inhibits Htt aggregation, while operating at suprastoichiometric concentrations. With this work, it is expected to unravel the relationship between HD and the S100B protein, which might constitute a foundation for the development of novel therapeutic approaches.Gomes, Cláudio M.Wanker, Erich E.Repositório da Universidade de LisboaBotelho, Marta Sofia Silva da Cruz202320232025-10-21T00:00:00Z2023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/62657enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-19T01:19:15Zoai:repositorio.ul.pt:10451/62657Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:38:59.077558Repositório 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 Investigations of S100 proteins and their role in huntingtin aggregation
title Investigations of S100 proteins and their role in huntingtin aggregation
spellingShingle Investigations of S100 proteins and their role in huntingtin aggregation
Botelho, Marta Sofia Silva da Cruz
Doença de Huntington
huntingtina
agregação proteica
S100B
Teses de mestrado - 2023
Departamento de Química e Bioquímica
title_short Investigations of S100 proteins and their role in huntingtin aggregation
title_full Investigations of S100 proteins and their role in huntingtin aggregation
title_fullStr Investigations of S100 proteins and their role in huntingtin aggregation
title_full_unstemmed Investigations of S100 proteins and their role in huntingtin aggregation
title_sort Investigations of S100 proteins and their role in huntingtin aggregation
author Botelho, Marta Sofia Silva da Cruz
author_facet Botelho, Marta Sofia Silva da Cruz
author_role author
dc.contributor.none.fl_str_mv Gomes, Cláudio M.
Wanker, Erich E.
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Botelho, Marta Sofia Silva da Cruz
dc.subject.por.fl_str_mv Doença de Huntington
huntingtina
agregação proteica
S100B
Teses de mestrado - 2023
Departamento de Química e Bioquímica
topic Doença de Huntington
huntingtina
agregação proteica
S100B
Teses de mestrado - 2023
Departamento de Química e Bioquímica
description Tese de mestrado, Bioquímica e Biomedicina , 2023, Universidade de Lisboa, Faculdade de Ciências
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023-01-01T00:00:00Z
2025-10-21T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/62657
url http://hdl.handle.net/10451/62657
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/embargoedAccess
eu_rights_str_mv embargoedAccess
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dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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