Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms

Bibliographic Details
Main Author: Morais, Sara Peres de
Publication Date: 2011
Format: Master thesis
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10362/6723
Summary: Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
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network_acronym_str RCAP
network_name_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
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spelling Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanismsAR-JPParkinUbiquitin-proteasome systemProtein aggregationNeuronal deathDissertação para obtenção do Grau de Mestre em Genética Molecular e BiomedicinaAutosomal recessive juvenile Parkinson disease (AR-JP) is mainly caused by mutations in PARK2. AR-JP presents with rigidity, bradykinesia and resting tremor, usually before age 40 years. Large PARK2 deletions account for 50% of the mutations identified in patients with AR-JP of Portuguese origin. The PARK2 gene encodes parkin, an E3 ubiquitin ligase, an important part of the cellular machinery that covalently tags target proteins with ubiquitin for degradation by the ubiquitinproteasome system (UPS), the main cellular protein degradation system responsible for targeted degradation of damaged and misfolded proteins. This project aims were: determine the breakpoints of the deletion found in Portuguese patients in order to identify the genomic mechanisms underlying these gene rearrangements and to explore the pathogenic mechanisms of parkin mutations by assessing the dynamics of formation and degradation of aggregates by UPS and also by determining its effects in the UPS degradation capacity and its relation with neuronal death. A successful approach was developed to narrow the deletion breakpoint intronic position. Cellular models expressing wild-type and mutant parkin were developed and characterized regarding mRNA and protein expression, as well as, aggregate formation, cell viability and proteasome activity. Our data show that the different studied mutations do not have an impact on cell viability, although resulted in differences in the number of cell with aggregates for the cells expressing N52MfsX29, L358RfsX77 and R275W mutants as well as in the number of aggregates present in each cell. We were also able to show that proteasome inhibition has as impact both in cell viability and in aggregate formation, resulting in decreased viability and increased aggregate formation. The study of the cellular mechanisms resulting in neuronal dysfunction is crucial for the identification of potential therapeutic targets for Parkinson disease.Faculdade de Ciências e TecnologiaAlonso, IsabelRUNMorais, Sara Peres de2012-01-13T11:18:14Z20112011-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/6723enginfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2024-05-22T17:09:57Zoai:run.unl.pt:10362/6723Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-28T16:40:47.201912Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
title Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
spellingShingle Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
Morais, Sara Peres de
AR-JP
Parkin
Ubiquitin-proteasome system
Protein aggregation
Neuronal death
title_short Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
title_full Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
title_fullStr Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
title_full_unstemmed Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
title_sort Juvenile Parkinson disease caused by parkin mutations: large deletions and pathogenic mechanisms
author Morais, Sara Peres de
author_facet Morais, Sara Peres de
author_role author
dc.contributor.none.fl_str_mv Alonso, Isabel
RUN
dc.contributor.author.fl_str_mv Morais, Sara Peres de
dc.subject.por.fl_str_mv AR-JP
Parkin
Ubiquitin-proteasome system
Protein aggregation
Neuronal death
topic AR-JP
Parkin
Ubiquitin-proteasome system
Protein aggregation
Neuronal death
description Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
publishDate 2011
dc.date.none.fl_str_mv 2011
2011-01-01T00:00:00Z
2012-01-13T11:18:14Z
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/10362/6723
url http://hdl.handle.net/10362/6723
dc.language.iso.fl_str_mv eng
language eng
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 Faculdade de Ciências e Tecnologia
publisher.none.fl_str_mv Faculdade de Ciências e Tecnologia
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
_version_ 1833596108838797312

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