Utilize este identificador para referenciar este registo: http://hdl.handle.net/10362/12438
Título: Exploring motor neuron degeneration in ALS - prevention by glycoursodeoxycholic acid and signaling to microglia
Autor: Cunha, Joana Carolina Marinho
Orientador: Brites, Dora
Vaz, Ana
Palavras-chave: SOD1 accumulation
Motor neuron degeneration
Mitochondrial dysfunction
GUDCA protective effects
Microglia activation
Data de Defesa: 2012
Editora: Faculdade de Ciências e Tecnologia
Resumo: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects mainly motor neurons. Neuronal pathology involves glial cells, in particular microglia. However it is not known how these cells interact with motor neurons. This is particularly important because till now no therapy has shown efficacy in ALS treatment. Here, we aim (i) to evaluate the suitability of NSC-34, a hybrid cell line of neuroblastoma and motor neurons, as a model of ALS, (ii) to explore the reactivity of microglia to the neuronal released factors and (iii) to assess the efficacy of glycoursodeoxycholic acid (GUDCA), which already has shown beneficial effects in several neurodevelopmental and neurodegenerative diseases. For that, we used NSC-34 cells transfected with human superoxide dismutase 1 (hSOD1), either wild type or mutated in G93A and the microglial N9 cell line. We observed mitochondrial dysfunction, energy impairment, NO production and metalloproteinase-9 activation, with consequent apoptosis in NSC-34/hSOD1G93A cells after 4 days of differentiation, in comparison to NSC-34/hSOD1wt cells. In addition, we established GUDCA as an anti-apoptotic and anti-inflammatory agent, able to prevent all the above mentioned features. Finally, released neuronal factors induced N9 microglia apoptosis and decreased their phagocytic ability. Overall, our results emphasize NSC-34/hSOD1G93A cells as a good ALS model, highlight GUDCA as having beneficial effects and point to microglia neuroprotective failure as a determinant mechanism of ALS pathogenesis.
Descrição: Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina
URI: http://hdl.handle.net/10362/12438
Aparece nas colecções:FCT: DCV - Dissertações de Mestrado

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