Analyzing how animal prions use existing cellular programs for release and intercellular spread

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Mammalian prions replicate by template-directed refolding of the normal cellular prion protein (PrPc) into the pathologic isoform PrPSc. There is growing evidence that this molecular process which uses transfer of information based solely upon protein conformations is not restricted to prion diseases. Prion-like phenomena have been described in various neurodegenerative diseases and in the context of memory storage and innate immunity. It is presently not understood how such protein aggregates are transferred between cells and which molecular and cellular machineries are involved. The proposed research program will address these questions, using mouse prions as a model system.****    The long-term goal of my research program is to better understand the cellular and molecular biology of prion infections. Our work has established that prions use cellular machineries for propagation, on the other hand they have to escape intracellular degradation. We have shown that autophagy, a basic cellular program for degradation and recycling, is involved in cellular clearance and propagation of prions. Our preliminary data suggest that autophagy, multi-vesicular bodies and prion release are interconnected. This leads us to propose as central hypothesis for the work over the next five years that release and intercellular spread of prions are regulated by the interplay between the autophagy machinery and exosomal release pathways.****     The current research program studies the molecular and cellular mechanisms involved in prion release, in the context of its interplay with autophagy. This will be investigated in the following aims:****1. to analyze how autophagy affects exosome formation and prion release in cell culture models,****2. to examine how this interplay impacts spread of infection to recipient cells and cell tropism, and****3. to study in animal models how compromised autophagy and exosomal release impact prion infection and prion strain modalities.****    Our research program will further define the life cycle of prions in and between cells and analyse another role of autophagy in prion infection. Our short-term goals are likely to produce new insights into prion release and spread between cells and tissues. They are nicely embedded into two of our overall long-term goals (autophagy and prion infections, prion protein trafficking) and are integrated into our overarching goal which is to characterize the molecular biology of prion infections.***