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Understanding lipid droplet biogenesis in the central nervous system of Drosophila models of Parkinson's disease

mar 15 déc 2020



Soutenance de M. Victor GIRARD sous la Direction de M. Bertrand MOLLEREAU

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Description générale

Interest for lipid droplets has recently spiked in the field of neurodegeneration with the finding that glial lipid droplets (LD) promote neuronal survival. Parkinson's disease (PD) is a neurodegenerative disorder associated with protein aggregation and deregulation of lipid storage. During my PhD, I investigated the contribution of neuronal and glial lipid droplets to neurodegeneration in genetic and toxin-induced Drosophila models of PD.
PD is characterized by the accumulation of alpha-synuclein (aSyn) in neuronal inclusions.
aSyn expression modulates lipid metabolism in cellular and animal models of PD by a mechanism that remains unclear. During my thesis, I found that expression of aSyn enhances
perilipin-dependent LD accumulation in Drosophila photoreceptor neurons. aSyn is colocalizes with perilipins on LD surface in Drosophila photoreceptor neurons as well as in
human neuroblastoma cells. I proposed that aSyn association with perilipins at the surface of LD, stabilize LD formation. Finally, modulating LD content in photoreceptor impacts aSyn
resistance to proteinase K suggesting that LDs are involved in the pathological aggregation of aSyn.
Glial cells are early sensor of central nervous system injuries that accumulate LD in response to neuronal stress to protect neurons from damages associated with lipid peroxidation. We found that loss of Split-ends (Spen), previously identified as a glial pro-survival factor during development, impairs LD homeostasis in adult Drosophila glial cell. In addition, spen mutant flies are more sensitive to paraquat, an herbicide linked with development of PD widely used in animal models to model PD. Thus Spen-mediated lipid metabolism functions could be important for neuroprotection in the context of PD.
Collectively these results provide new evidences for the importance of LDs in neurons and glial cells for the development of PD.

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