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Physiopathologie et thérapeutique des prions humains : une approche cellulaire

Abstract : Prion diseases are fatal transmissible neurodegenerative disorders, with no effective treatment. Brain lesions include neuronal vacuolization, astrogliosis, neuronal loss and the accumulation of PrPSc, an abnormal isoform of the host-encoded cellular prion protein (PrPc). Some forms of prion diseases are associated with tau fibrillar pathology similar to that observed in Alzheimer’s disease except that Abeta peptides are replaced by PrPsc. Here we used a primary neuronal cultures to first explore the interplay between the formation of prion protein assemblies and the occurrence of tau pathology, and secondly to evaluate in vitro human strain propagation and the efficiency of some antiprion compounds towards human prions. We showed that tau hyperphosphorylation in response to recombinant PrPs exposition was mutation-dependent, conformation-dependent and varied with the PrPc expression level of exposed neurons. This effect was mediated by PDK1 kinase. We also demonstrated for the first time that human prion isolates could propagate in an in vitro model. This model was also useful to evaluate the efficacy of antiprion compounds that was further validated in vivo. Our results help us to better understand the amyloid protein-tau physiopathology interplay and provide a useful and unique tool for fast evaluation of therapeutic compounds active against human prion strains in a repositioning strategy in such rare but devastating diseases.
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Submitted on : Monday, March 25, 2019 - 1:01:18 AM
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  • HAL Id : tel-02078046, version 1


Alexianne Gougerot. Physiopathologie et thérapeutique des prions humains : une approche cellulaire. Neurosciences [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066087⟩. ⟨tel-02078046⟩



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