Unravelling BRI2 role in neuronal differentiation

Detalhes bibliográficos
Autor(a) principal: Monteiro, Bruno André Catarino Silva
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10773/35958
Resumo: Adult neurogenesis describes the process in which new neurons are formed from neuronal stem cells past the early developmental period. In humans, adult neurogenesis was thought to occur exclusively within the subventricular zone and subgranular zone niches, however, novel neurogenic niches, such as the substancia nigra, cortex and hypothalamus, have been proposed. This process requires the migration of committed proliferating neuronal precursors into existing neuronal circuits, where they differentiate into mature neurons and are synaptically integrated. Abnormalities in any of these stages impair neurogenesis and could compromise brain function. In fact, impaired neurogenesis seems to be a common hallmark in several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Hence, researchers are trying to find new pro-neurogenic therapeutic approaches to increase basal levels of neurogenesis in patients with neurodegenerative diseases. These include lifestyle interventions, pharmacological strategies, gene therapies, stem cell therapies and glia-to-neuron reprogramming. Nonetheless, currently there is not an available therapy for neurodegenerative diseases that targets neurogenesis. BRI2 is a ubiquitous type II transmembrane protein which is highly expressed in the central nervous system, namely cortex and hippocampus. This protein undergoes regulated intramembrane proteolysis which results in the shedding of several short peptides. The precise physiological function of BRI2 and its proteolytic fragments remains elusive, however, a putative role in neuronal differentiation has recently been proposed by our group. Indeed, BRI2 expression and processing were found to be substantially increased during the neuronal maturation process. Therefore, promotion of neuronal differentiation through a BRI2-dependent therapeutic strategy might prove to be a useful method to increase neurogenic activity. Herein, we investigated the effect of a recombinant BRI2 peptide fragment on the differentiation phenotype of the neuroblastoma-like SH-SY5Y cell line. The results obtained indicate that the produced recombinant peptide at doses and times incubated does not have an effect in the SH-SY5Y differentiation, as no significant differences were observed when compared to the control. Nevertheless, given the previously established relevant role of BRI2 and its proteolytic processing in neuronal maturation, more research should be conducted before ruling out BRI2 as a modulator of neuronal differentiation.
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spelling Unravelling BRI2 role in neuronal differentiationNeurogenesisNeuronal differentiationNeuritogenesisBRI2SH-SY5YProteolytic processingAdult neurogenesis describes the process in which new neurons are formed from neuronal stem cells past the early developmental period. In humans, adult neurogenesis was thought to occur exclusively within the subventricular zone and subgranular zone niches, however, novel neurogenic niches, such as the substancia nigra, cortex and hypothalamus, have been proposed. This process requires the migration of committed proliferating neuronal precursors into existing neuronal circuits, where they differentiate into mature neurons and are synaptically integrated. Abnormalities in any of these stages impair neurogenesis and could compromise brain function. In fact, impaired neurogenesis seems to be a common hallmark in several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Hence, researchers are trying to find new pro-neurogenic therapeutic approaches to increase basal levels of neurogenesis in patients with neurodegenerative diseases. These include lifestyle interventions, pharmacological strategies, gene therapies, stem cell therapies and glia-to-neuron reprogramming. Nonetheless, currently there is not an available therapy for neurodegenerative diseases that targets neurogenesis. BRI2 is a ubiquitous type II transmembrane protein which is highly expressed in the central nervous system, namely cortex and hippocampus. This protein undergoes regulated intramembrane proteolysis which results in the shedding of several short peptides. The precise physiological function of BRI2 and its proteolytic fragments remains elusive, however, a putative role in neuronal differentiation has recently been proposed by our group. Indeed, BRI2 expression and processing were found to be substantially increased during the neuronal maturation process. Therefore, promotion of neuronal differentiation through a BRI2-dependent therapeutic strategy might prove to be a useful method to increase neurogenic activity. Herein, we investigated the effect of a recombinant BRI2 peptide fragment on the differentiation phenotype of the neuroblastoma-like SH-SY5Y cell line. The results obtained indicate that the produced recombinant peptide at doses and times incubated does not have an effect in the SH-SY5Y differentiation, as no significant differences were observed when compared to the control. Nevertheless, given the previously established relevant role of BRI2 and its proteolytic processing in neuronal maturation, more research should be conducted before ruling out BRI2 as a modulator of neuronal differentiation.A neurogénese adulta descreve o processo no qual novos neurónios são formados a partir de células estaminais neuronais, após o período inicial de desenvolvimento. Nos humanos pensava-se que a neurogénese adulta ocorria exclusivamente nos nichos da zona subventricular e zona subgranular, no entanto, a existência de novos nichos neurogénicos, como a substancia nigra, córtex e hipotálamo, tem sido proposta. Este processo requer a migração de precursores neuronais comprometidos com a linhagem de células neuronais para circuitos neuronais existentes, onde estes se diferenciam em neurónios maduros e são sinapticamente integrados. Uma anomalia em qualquer uma destas etapas prejudica a neurogénese e pode comprometer a função cerebral. De facto, a diminuição da atividade neurogénica parece ser uma característica comum em várias doenças neurodegenerativas, incluindo as doenças de Alzheimer, Parkinson e Huntington. Consequentemente, investigadores estão à procura de novas terapias pró-neurogénicas para aumentar os níveis basais de neurogénese em pacientes com doenças neurodegenerativas. Estas terapias incluem: modificações de estilos de vida, estratégias farmacológicas, terapias génicas, terapias de células estaminais, e reprogramação de glia em neurónios. Não obstante, atualmente não existe uma terapia disponível para doenças neurodegenerativas dirigida à neurogénese. A BRI2 é uma proteína transmembranar do tipo II com expressão ubíqua, altamente expressa no sistema nervoso central, nomeadamente no córtex e hipocampo. Esta proteína sofre proteólise intramembranar regulada o que resulta na libertação de vários péptidos. A função fisiológica exata da BRI2 e dos seus fragmentos proteolíticos continua por identificar, no entanto, foi recentemente proposto pelo nosso grupo um possível papel na diferenciação neuronal. De facto, a expressão e processamento de BRI2 encontra-se substancialmente elevada durante o processo de maturação neuronal. Portanto, a promoção de diferenciação neuronal através de uma estratégia terapêutica baseada em BRI2 pode revelar-se um método útil para aumentar a atividade neurogénica. Neste trabalho investigámos o efeito de um péptido recombinante de um fragmento da BRI2 na diferenciação da linha celular SH-SY5Y. Os resultados obtidos indicam que o péptido produzido nas doses e tempos em que foi incubado não produz um efeito na diferenciação das células SH-SY5Y, visto que não foram observadas diferenças significativas em relação ao controlo. Contudo, dado o papel relevante estabelecido anteriormente para a BRI2 e o seu processamento proteolítico na maturação neuronal, devem ser realizados mais estudos antes de excluir a BRI2 como um modulador da diferenciação neuronal.2025-01-04T00:00:00Z2022-12-20T00:00:00Z2022-12-20info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/35958engMonteiro, Bruno André Catarino Silvainfo: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:RCAAP2024-05-06T04:42:28Zoai:ria.ua.pt:10773/35958Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-06T04:42:28Repositório 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 Unravelling BRI2 role in neuronal differentiation
title Unravelling BRI2 role in neuronal differentiation
spellingShingle Unravelling BRI2 role in neuronal differentiation
Monteiro, Bruno André Catarino Silva
Neurogenesis
Neuronal differentiation
Neuritogenesis
BRI2
SH-SY5Y
Proteolytic processing
title_short Unravelling BRI2 role in neuronal differentiation
title_full Unravelling BRI2 role in neuronal differentiation
title_fullStr Unravelling BRI2 role in neuronal differentiation
title_full_unstemmed Unravelling BRI2 role in neuronal differentiation
title_sort Unravelling BRI2 role in neuronal differentiation
author Monteiro, Bruno André Catarino Silva
author_facet Monteiro, Bruno André Catarino Silva
author_role author
dc.contributor.author.fl_str_mv Monteiro, Bruno André Catarino Silva
dc.subject.por.fl_str_mv Neurogenesis
Neuronal differentiation
Neuritogenesis
BRI2
SH-SY5Y
Proteolytic processing
topic Neurogenesis
Neuronal differentiation
Neuritogenesis
BRI2
SH-SY5Y
Proteolytic processing
description Adult neurogenesis describes the process in which new neurons are formed from neuronal stem cells past the early developmental period. In humans, adult neurogenesis was thought to occur exclusively within the subventricular zone and subgranular zone niches, however, novel neurogenic niches, such as the substancia nigra, cortex and hypothalamus, have been proposed. This process requires the migration of committed proliferating neuronal precursors into existing neuronal circuits, where they differentiate into mature neurons and are synaptically integrated. Abnormalities in any of these stages impair neurogenesis and could compromise brain function. In fact, impaired neurogenesis seems to be a common hallmark in several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Hence, researchers are trying to find new pro-neurogenic therapeutic approaches to increase basal levels of neurogenesis in patients with neurodegenerative diseases. These include lifestyle interventions, pharmacological strategies, gene therapies, stem cell therapies and glia-to-neuron reprogramming. Nonetheless, currently there is not an available therapy for neurodegenerative diseases that targets neurogenesis. BRI2 is a ubiquitous type II transmembrane protein which is highly expressed in the central nervous system, namely cortex and hippocampus. This protein undergoes regulated intramembrane proteolysis which results in the shedding of several short peptides. The precise physiological function of BRI2 and its proteolytic fragments remains elusive, however, a putative role in neuronal differentiation has recently been proposed by our group. Indeed, BRI2 expression and processing were found to be substantially increased during the neuronal maturation process. Therefore, promotion of neuronal differentiation through a BRI2-dependent therapeutic strategy might prove to be a useful method to increase neurogenic activity. Herein, we investigated the effect of a recombinant BRI2 peptide fragment on the differentiation phenotype of the neuroblastoma-like SH-SY5Y cell line. The results obtained indicate that the produced recombinant peptide at doses and times incubated does not have an effect in the SH-SY5Y differentiation, as no significant differences were observed when compared to the control. Nevertheless, given the previously established relevant role of BRI2 and its proteolytic processing in neuronal maturation, more research should be conducted before ruling out BRI2 as a modulator of neuronal differentiation.
publishDate 2022
dc.date.none.fl_str_mv 2022-12-20T00:00:00Z
2022-12-20
2025-01-04T00:00:00Z
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dc.language.iso.fl_str_mv eng
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