A carregar...
Publicação
Drosophila models of neuromuscular disorders: From morphology to behavior
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 4.62 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
RESUMO: As doenças neurodegenerativas, que podem originar ataxia ou demência, são doenças incuráveis e debilitantes que têm como consequência a degeneração progressiva seguida de morte neuronal. O mecanismo que provoca a neurodegeneração não é totalmente conhecido, sabendo-se apenas que está associado a múltiplas vias e contribuições genéticas. Dada a complexidade e variedade de mecanismos patológicos, um tratamento eficaz para este tipo de distúrbio é difícil de alcançar. Uma forma de contornar esta dificuldade, é através da promoção da complexidade neuronal de células ainda funcionais como meio de retardamento da progressão da doença. Ao caracterizar a morfologia e composição sináptica de vários modelos de neurodegeneração usando Drosophila melanogaster, o objetivo é averiguar se existe um alvo específico comum que possa retardar este sintoma. Para isto, foi utilizado como recurso um knocdown neuronal de genes associados a duas doenças neuromotoras, a Neurodegeneração associada à cinase do Ácido Pantoténico e a Paraplegias Espáticas Hereditárias. Para além disto, análises comportamentais locomotoras utilizando vários ensaios com diferentes sensibilidades foram realizadas em várias fases do ciclo de vida da mosca da fruta, através da utilização de knocdown específico para neurónio e células da glia para modelos de Esclerose Lateral Amiotrófica, Atrofia Muscular Espinhal, PKAN e HSP. Aqui, verificou-se que todos os genótipos estão associados a uma função locomotora diminuída que parece ser dependente das proteínas que foram anuladas nos neurônios e na glia.
Este trabalho contribui para a compreensão da composição sináptica dos modelos de doença acima referidos que poderá ser utilizado como fator determinante para encontrar uma via que contorne a neurodegeneração através do aumento da complexidade neuronal. Para a PKAN, dado que muito pouco se sabe acerca desta doença, este trabalho contribui para a perceção de mais uma via que induz neurodegeneração e quais as alterações sinápticas possivelmente associadas.
ABSTRACT: Neurodegenerative disorders are one of the most common illness manifestations worldwide. They have a chronic and progressive display, characterized by synaptic malfunction that then evolve to irreversible neuronal death. The mechanism behind neurodegeneration is not fully understood and can have several associated pathways and genetic contributions. Given that a treatment suitable for all forms of neurodegeneration is hard to get, one idea to overcome this issue is to promote neuronal complexity in the non-affected neurons, to try to delay the progression of these type of disorders. By characterizing the synaptic composition of several examples of Drosophila melanogaster models of neurodegenerative diseases, we intended to explore whether there is a specific target that can be targeted to slow neurodegeneration. Using cell type specific RNAi, we induce neuronal knockdown of genes associated with Pantothenate Kinase Associated Neurodegeneration and Hereditary Spastic Paraplegia. Several features of synaptic morphological and composition were addressed at the Drosophila NMJ. Also, behavior analyses using several assays with different sensitivities were performed in several stages of the Drosophila life cycle. Using neuronal or glial specific RNAi against proteins associated with Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, PKAN and HSP, we show that all of these genotypes are associated with impaired locomotor function that seems to be dependent on the proteins that were knockdown in neurons and in wrapping glia cells. This work contributes to the understanding of the synaptic composition of HSP and PKAN disease models, that can be used to help us target downstream pathways, that will lead to increase structural plasticity as a way to promote neuronal complexity and overcome neurodegeneration. For PKAN, as very little information is available, it contributes to the understanding of the underlying causes of the disorder and to provide insights in which are the synaptic alterations behind patients with mutations in PanK2.
ABSTRACT: Neurodegenerative disorders are one of the most common illness manifestations worldwide. They have a chronic and progressive display, characterized by synaptic malfunction that then evolve to irreversible neuronal death. The mechanism behind neurodegeneration is not fully understood and can have several associated pathways and genetic contributions. Given that a treatment suitable for all forms of neurodegeneration is hard to get, one idea to overcome this issue is to promote neuronal complexity in the non-affected neurons, to try to delay the progression of these type of disorders. By characterizing the synaptic composition of several examples of Drosophila melanogaster models of neurodegenerative diseases, we intended to explore whether there is a specific target that can be targeted to slow neurodegeneration. Using cell type specific RNAi, we induce neuronal knockdown of genes associated with Pantothenate Kinase Associated Neurodegeneration and Hereditary Spastic Paraplegia. Several features of synaptic morphological and composition were addressed at the Drosophila NMJ. Also, behavior analyses using several assays with different sensitivities were performed in several stages of the Drosophila life cycle. Using neuronal or glial specific RNAi against proteins associated with Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, PKAN and HSP, we show that all of these genotypes are associated with impaired locomotor function that seems to be dependent on the proteins that were knockdown in neurons and in wrapping glia cells. This work contributes to the understanding of the synaptic composition of HSP and PKAN disease models, that can be used to help us target downstream pathways, that will lead to increase structural plasticity as a way to promote neuronal complexity and overcome neurodegeneration. For PKAN, as very little information is available, it contributes to the understanding of the underlying causes of the disorder and to provide insights in which are the synaptic alterations behind patients with mutations in PanK2.
Descrição
Palavras-chave
NMJ HSP PKAN Neurodegeneração Doenças neurodegenerativas Atividade sináptica Neurodegeneration Neurodegenerative disorders Synaptic activity