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Exploring the role of MFG-E8 in ALS
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Resumo(s)
A Esclerose Lateral Amiotrófica é uma doença neurodegenerativa rara e fatal caraterizada pela degeneração tanto dos neurónios motores superiores como dos neurónios motores inferiores. Para além dos neurónios, a microglia está também comprometida considerando a falência das suas funções vitais no sistema nervoso central, sendo uma delas a fagocitose. A função fagocítica da microglia pode ser mediada por uma proteína denominada de glóbulo de gordura do leite-fator de crescimento epidérmico 8 ou MFG-E8.
Esta proteína é produzida pela microglia e é libertada para o meio extracelular, onde vai exercer a sua função enquanto ponte entre a célula apoptótica e a microglia, facilitando a função fagocitíca da microglia. Para além da microglia, os astrócitos também podem produzir MFG-E8 e libertá-la para o meio extracelular, exercendo um papel adicional à fagocitose pela microglia. Os nossos estudos anteriores demonstraram que a expressão génica da MFG-E8 está diminuída na medula espinhal de ratinhos mSOD1 o que indica que a fagocitose pode estar comprometida.
Os nossos resultados mostram que a expressão génica da MFG-E8 está diminuída tanto nos astrócitos derivados da medula espinhal como nos do córtex de ratinhos mSOD1. Relativamente à expressão proteica, esta está diminuída nos astrócitos derivados do córtex o que indica que estas células não estão a contribuir para a produção da proteína e, por isso, o seu papel como facilitadores da função fagocítica da microglia pode também estar comprometido. Para além disto, os nossos resultados mostraram ainda que existe um aumento na expressão proteica na microglia mSOD1 de 2 dias e 16 dias derivada da medula espinhal. Este aumento pode dever-se a uma retenção da proteína na célula, estando assim impedida de realizar a sua função no meio extracelular, como interveniente da fagocitose das células apoptóticas.
Este estudo comprova que a MFG-E8 pode estar desregulada na Esclerose Lateral Amiotrófica, podendo ser um dos mecanismos da patogenicidade da doença.
Amyotrophic Lateral Sclerosis is a rare and fatal neurodegenerative disease characterized by degeneration of both upper and lower motor neurons. In addition to neurons, microglia are also compromised considering the failure of their vital functions in the central nervous system, namely the phagocytosis as one of them. The phagocytic function of microglia can be mediated by a protein called the milk fat globule-epidermal growth factor 8 or MFG-E8. This protein is produced by the microglia and is released to the extracellular environment, where it will play its role as a bridge between the apoptotic cell and the microglia, facilitating the phagocytic function of microglia. In addition to microglia, astrocytes can also produce MFG-E8 and release it to the extracellular medium, playing an additional role in phagocytosis by microglia. Our previous studies have shown that MFG-E8 gene expression is decreased in the spinal cord of mSOD1 mice indicating that phagocytosis may be compromised. Our results show that MFG-E8 gene expression is decreased in both astrocytes derived from the spinal cord and in the cortex of mSOD1 mice. Regarding protein expression, this is decreased in cortex-derived astrocytes, which indicates that these cells are not contributing to protein production and, therefore, their role as facilitators of phagocytic function of microglia may also be compromised. Furthermore, our results also showed that there is an increase in protein expression in in the 2 days and 16 days spinal mSOD1 microglia. This increase may be due to a retention of the protein in the cell, thus preventing it from performing its function in the extracellular environment, as a driver in the phagocytosis of apoptotic cells. This study suggests that MFG-E8 may be dysregulated in Amyotrophic Lateral Sclerosis and may be one of the pathogenicity mechanisms of the disease.
Amyotrophic Lateral Sclerosis is a rare and fatal neurodegenerative disease characterized by degeneration of both upper and lower motor neurons. In addition to neurons, microglia are also compromised considering the failure of their vital functions in the central nervous system, namely the phagocytosis as one of them. The phagocytic function of microglia can be mediated by a protein called the milk fat globule-epidermal growth factor 8 or MFG-E8. This protein is produced by the microglia and is released to the extracellular environment, where it will play its role as a bridge between the apoptotic cell and the microglia, facilitating the phagocytic function of microglia. In addition to microglia, astrocytes can also produce MFG-E8 and release it to the extracellular medium, playing an additional role in phagocytosis by microglia. Our previous studies have shown that MFG-E8 gene expression is decreased in the spinal cord of mSOD1 mice indicating that phagocytosis may be compromised. Our results show that MFG-E8 gene expression is decreased in both astrocytes derived from the spinal cord and in the cortex of mSOD1 mice. Regarding protein expression, this is decreased in cortex-derived astrocytes, which indicates that these cells are not contributing to protein production and, therefore, their role as facilitators of phagocytic function of microglia may also be compromised. Furthermore, our results also showed that there is an increase in protein expression in in the 2 days and 16 days spinal mSOD1 microglia. This increase may be due to a retention of the protein in the cell, thus preventing it from performing its function in the extracellular environment, as a driver in the phagocytosis of apoptotic cells. This study suggests that MFG-E8 may be dysregulated in Amyotrophic Lateral Sclerosis and may be one of the pathogenicity mechanisms of the disease.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Amyotrophic lateral sclerosis MFG-E8 Phagocytosis Microglia Astrocytes Mestrado integrado - 2021