Caputo, Anna (2009) Pathogenetic mechanisms in neurodegenerative processes induced by prion proteins. [Tesi di dottorato] (Unpublished)

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During the period of my thesis I have used multiple approaches and techniques to study different aspects of prion trafficking in order to analyze different hypothesis on the pathogenetic mechanisms of prion diseases. In summary I found that: 1. The anchorless form of PrPC (PrPΔGPI) follows different intracellular pathways compared to the wild type protein. Thus, considering the data present in literature, we formulated the hypothesis that in order to exert the neurotoxic effect following prion infection PrPC and/or PrPSc have to localize at the plasma membrane in specific domains of the plasma membrane. 2. PrPC endocytosis depends on both clathrin and rafts but not on caveolae. Therefore PrPC can be internalized by both a clathrin and raft mediated pathways although these different routes can also converge in a unique pathway. We speculate that undertaking a specific pathway can depend on the cell types and might have important consequences on the conversion process and toxicity of PrP. 3. The Endosomal Recycling Compartment is a site where the pathogenic conversion occurs. This is a mayor discovery since opens a new avenue towards the identification of factors involved in prion conversion and the development of therapeutics. 4. I have set up a new infection model of primary hippocampal neuronal cultures. This system will allow a more physiological study of the trafficking and mechanisms of neurodegeneration of prions. 5. PrPC co-immunoprecipitate with Dpl in membrane rafts. This data propose a mechanism for the genetic interaction between PrPC and Dpl and strengthen the hypothesis of the necessity of PrPC, possibly as signaling molecule, in the pathogenesis of neurodegeneration . 6. I also gave a contribution to the discovery that Tunneling Nanotubes are the likely mechanism to spread prions from the periphery to the CNS

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