Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis

Detalhes bibliográficos
Autor(a) principal: Marçal, Ana Rita Miranda
Data de Publicação: 2020
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/47775
Resumo: Tese de mestrado, Bioquímica (Bioquímica Médica) Universidade de Lisboa, Faculdade de Ciências, 2020
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spelling Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesisDoenca de Parkinsonalfa-sinucleinaEnzima degradante da insulinaDiabetes mellitus tipo 2Teses de mestrado - 2020Departamento de Química e BioquímicaTese de mestrado, Bioquímica (Bioquímica Médica) Universidade de Lisboa, Faculdade de Ciências, 2020Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. It is typically known for its motor features like bradykinesia and tremors. However, non-motor symptoms are also present in the disease such as constipation, hyposmia and depression. The principal hallmark of PD is the accumulation and aggregation of alpha-synuclein (aSyn) in the brain, triggering dopaminergic neuronal death. 90% of PD cases are of sporadic origin, and the molecular events that trigger the disease are still unknown. Currently, there is no effective therapeutics able to stop or delay the progression of this disease. Therefore, there is an unmet urgent medical need to identify novel therapeutic avenues that can modulate disease progression. The evaluation of how PD risk factors have an impact in the disease may allow for a better understanding of the molecular events underlying disease onset and progression. Notably, type II diabetes mellitus (T2DM) has been considered an important risk factor for PD. In fact, T2DM patients between 25-45 years old present 380% higher risk of developing PD. Insulin-degrading enzyme (IDE), which is typically known for the proteolytic degradation of insulin, is highly dysregulated in T2DM. It is a multifunctional enzyme, also playing heat-shock responses including chaperone and ubiquitin-activating enzyme activities. Recently, IDE was determined to interact with aSyn and suppress its aggregation in vitro in a non-proteolytic manner, and that IDE and aSyn levels are inversely correlated in human β-cells. Provided that the levels of IDE are decreased in T2DM patients’ pancreas, where aSyn is more oligomerized, it is important to understand if an IDE loss of function also occurs in the brain and if it has an impact in PD pathogenesis. Altogether, we hypothesize that IDE potentiation may protect from aSyn pathogenesis. To validate this hypothesis, we used H4 cells transfected with IDE WT or with a proteolytic inactive variant of IDE (E111Q) and evaluated their protective potential against aSyn cytotoxicity, accumulation and insolubility. A ~6-fold expression of IDE variants did not reduce cytotoxicity in both control cells (GFP) or aSyn expressing cells (aSyn+GFP). They also did not modulate aSyn levels, but both IDE variants were capable of reducing aSyn insolubility. For a lower expression level of the IDE variants, IDE WT but not E111Q was able to reduce the small toxicity induced by aSyn. To potentiate aSyn pathogenesis, we challenged cells to methylglyoxal. Both variants were able to decrease MGO-induced toxicity in both control and aSyn-expressing cells. In these conditions, IDE was not able to modulate both aSyn levels and insolubility. Our findings suggest that IDE may act as a chaperone or dead-end chaperone by suppressing amyloid formation, leading to a decrease on aSyn toxicity. Altogether, we conclude that IDE may play an important role in protecting against aSyn toxicity and aggregation in brain cellular models and it may represent a valid target able to modulate PD’s progression.Miranda, Hugo Miguel Vicente, 1982-Gomes, Cláudio M.Repositório da Universidade de LisboaMarçal, Ana Rita Miranda2021-05-11T17:52:11Z202020202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/47775TID:202695905engmetadata only accessinfo: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:RCAAP2023-11-08T16:50:57Zoai:repositorio.ul.pt:10451/47775Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:46.755579Repositório 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 Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
title Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
spellingShingle Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
Marçal, Ana Rita Miranda
Doenca de Parkinson
alfa-sinucleina
Enzima degradante da insulina
Diabetes mellitus tipo 2
Teses de mestrado - 2020
Departamento de Química e Bioquímica
title_short Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
title_full Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
title_fullStr Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
title_full_unstemmed Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
title_sort Insulin-Degrading Enzyme as a suppressor of alpha-synuclein pathogenesis
author Marçal, Ana Rita Miranda
author_facet Marçal, Ana Rita Miranda
author_role author
dc.contributor.none.fl_str_mv Miranda, Hugo Miguel Vicente, 1982-
Gomes, Cláudio M.
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Marçal, Ana Rita Miranda
dc.subject.por.fl_str_mv Doenca de Parkinson
alfa-sinucleina
Enzima degradante da insulina
Diabetes mellitus tipo 2
Teses de mestrado - 2020
Departamento de Química e Bioquímica
topic Doenca de Parkinson
alfa-sinucleina
Enzima degradante da insulina
Diabetes mellitus tipo 2
Teses de mestrado - 2020
Departamento de Química e Bioquímica
description Tese de mestrado, Bioquímica (Bioquímica Médica) Universidade de Lisboa, Faculdade de Ciências, 2020
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020-01-01T00:00:00Z
2021-05-11T17:52:11Z
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/10451/47775
TID:202695905
url http://hdl.handle.net/10451/47775
identifier_str_mv TID:202695905
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv metadata only access
info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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
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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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