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Theses

Maladies neurodégénératives et stress oxydant

Abstract : Alzheimer's disease and prion diseases are incurable neurodegenerative diseases associated with the transconformation of a polypeptide: the Aß peptide and the prion protein (PrP) respectively. These misfolded polypeptides then form different aggregates in the brain, leading to neuronal death. In a healthy individual, PrP has a neuroprotective function, but in patients suffering from Alzheimer or prion diseases, the toxicity of some pathological aggregates is mediated by this protein. Moreover, both pathologies are associated with an early chronic oxidative stress, that is toxic. It can promote and be promoted by protein aggregation, without the aggregates involved in this vicious circle being precisely identified.To study oxidative stress in these diseases, I developed innovative cellular models to monitor oxidation markers in real time, and bioinformatic tools to analyze the results. My work shows that the unique expression of the healthy form of Aß or PrP protects cells from an exogenous oxidant. However, the addition to the culture medium of the same cells of recombinant Aß and PrP promotes the appearance of oxidative stress, only for cells expressing normal PrP. This effect is visible for A in the form of amyloid fibrils, and for PrP in the form of monomer, oligomers and potentially amyloid fibrils. This work thus validates the central role of normal PrP in physiology and pathology. My results could suggest a role of glutathione peroxidases in mediating the protective effect of normal PrP, and an activation of NADPH oxidases via PrP in the presence of pathological aggregates.
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Submitted on : Tuesday, March 30, 2021 - 9:41:24 AM
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Elise Lévy. Maladies neurodégénératives et stress oxydant. Neurosciences [q-bio.NC]. Université Paris-Saclay, 2020. Français. ⟨NNT : 2020UPASB028⟩. ⟨tel-03185033⟩

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