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Genetic analysis of glial cells in Health and Disease using Drosophila melanogaster as a model

Student thesis: Doctoral ThesisDoctor of Philosophy

The increasing understanding of neurodegenerative diseases at the cellular and molecular level has directed part of the research toward the investigation of the role of glial cells in the pathogenesis. Specific impairment of this long-time neglected cell type has revealed that it was much more than just glue and is now considered a major player in either triggering defects or in the progression of nervous system disorders. My thesis proposes to investigate the role of glial cells in disease condition but also in “healthy” brain in order to uncover new mechanisms important in the complex interactions between glia and neurons. Using glial expression of the polyglutamine Atrophin as a disease model, I first characterized the importance and the participation of each glial subtype in the reduction of the Drosophila lifespan. The use of different specific glial drivers to express the mutated protein showed that the astrocyte-like glia might be the most important cell type, but not the only one, involved in the decrease of the lifespan. Then, using an unbiased RNAi-based screening method, I modulated neuronal gene expression in a newly established Drosophila model with impaired glial functions via the expression of a newly engineered polyglutamine Atrophin. Lifespan was used as a read out for the impairment of the nervous system homeostasis, leading to the discovery of genes able to modulate the reduction of the lifespan due to glial toxicity. The diversity of the candidate gene functions highlights the complexity of glia-neuron interactions involved in the disease and demonstrates that more investigation need to be done in order to fully understand the multifactorial causes of neuronal dysfunctions or death in neurodegenerative diseases. Beside the impairment of Drosophila glial cells in a disease condition, I also investigated the role of glial cells in adult CNS homeostasis. Via the downregulation of a transcription factor common and specific to all adult glial cells, called repo, I uncovered new glial functions involved in general brain homeostasis. Finally, I emphasize the importance of non-autonomous effect of glial transcription in neuronal function and morphology, using the visual system as a model. The results suggest that repo-dependent glial function is constantly needed during adult life in order to maintain a functional nervous system.
Original languageEnglish
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Award date2016

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