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In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs

Bibliographic Details
Main Author: Vieira, Adriana Andrade
Publication Date: 2020
Format: Master thesis
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/47760
Summary: Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020
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spelling In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCsSíndrome de AngelmanUBE3Aimprinting genómicoiPSCsdiferenciação neuronalmodelos de doençadoença neurológicaTeses de mestrado - 2020Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020Angelman syndrome (AS) is a rare neurodevelopmental disorder with no cure, characterized by a severe developmental delay, speech impairment, motor dysfunction, and a characteristic happy behavior. AS is caused by the loss of functional UBE3A protein, an E3 ubiquitin ligase that targets proteins for degradation by the ubiquitin-proteasome system. Disruption of UBE3A activity in neurons impairs ubiquitination leading to accumulation of UBE3A-specific targets which results in neuronal dysfunction. The UBE3A gene undergoes tissue-specific genomic imprinting, an epigenetic phenomenon that leads to parent-of-origin-specific monoallelic expression. Thus, UBE3A is exclusively expressed from the maternally inherited allele in mature neurons, since the paternal allele is silenced upon neuronal differentiation due to transcriptional interference of an antisense RNA called UBE3A-ATS. Loss of maternal UBE3A allele results in complete absence of UBE3A protein ultimately leading to AS. Most of what we know about AS has been studied in animal models, however, this pre-clinical model has several limitations for direct translation to the human disease. Recently, somatic cell reprogramming technology and neuronal differentiation protocols have contributed to overcome such difficulty and establish in vitro models using patient-derived induced pluripotent stem cells (iPSCs). These models enable the generation of disease-relevant cells in limitless amounts while faithfully recapitulating neuronal developmental hallmarks, which allows the detailed elucidation of the disease mechanisms responsible for the clinical features observed in patients. In this project, we submitted healthy control and AS-derived iPSCs to a neuronal differentiation protocol for 80 days to obtain fully mature neurons. Our data suggest AS-derived neuronal cultures display increased neuronal apoptosis, enhanced gliogenesis and persistence or progenitor-like neural rosettes at the final stages of differentiation. We hypothesize that loss of UBE3A function impairs neuronal viability and consequently prompts neural progenitors to continue proliferating and differentiating, causing a precocious neuro-to-glia switch. Our results show the suitability of patient-derived iPSCs to be used as a disease modelling approach to study Angelman syndrome and future works will use this system to tackle the pathophysiological mechanisms at the molecular level that causes AS.Bekman, EvgueniaRodrigues, Maria Gabriela, 1965-Repositório da Universidade de LisboaVieira, Adriana Andrade2022-12-31T01:31:31Z202020202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/47760TID:202693422enginfo: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:RCAAP2025-03-17T14:33:14Zoai:repositorio.ulisboa.pt:10451/47760Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T03:15:16.590274Repositórios 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 In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
title In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
spellingShingle In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
Vieira, Adriana Andrade
Síndrome de Angelman
UBE3A
imprinting genómico
iPSCs
diferenciação neuronal
modelos de doença
doença neurológica
Teses de mestrado - 2020
Departamento de Biologia Vegetal
title_short In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
title_full In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
title_fullStr In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
title_full_unstemmed In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
title_sort In vitro Modeling of Angelman Syndrome using the Neural Commitment of Patient-Specific iPSCs
author Vieira, Adriana Andrade
author_facet Vieira, Adriana Andrade
author_role author
dc.contributor.none.fl_str_mv Bekman, Evguenia
Rodrigues, Maria Gabriela, 1965-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Vieira, Adriana Andrade
dc.subject.por.fl_str_mv Síndrome de Angelman
UBE3A
imprinting genómico
iPSCs
diferenciação neuronal
modelos de doença
doença neurológica
Teses de mestrado - 2020
Departamento de Biologia Vegetal
topic Síndrome de Angelman
UBE3A
imprinting genómico
iPSCs
diferenciação neuronal
modelos de doença
doença neurológica
Teses de mestrado - 2020
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020-01-01T00:00:00Z
2022-12-31T01:31:31Z
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/10451/47760
TID:202693422
url http://hdl.handle.net/10451/47760
identifier_str_mv TID:202693422
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.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_ 1833601641331294208

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