Final Report Summary - PROCUREPM (Protein Misfolding: Prion-like Propagation and Cure. Implications for Neurodegenerative Diseases.) The goal of this grant was to understand, how misfolded proteins, associated with the pathogenesis of most neurodegenerative diseases, propagate in a prion-like manner (i) and to identify strategies that could lead to cure protein misfolding (ii).With this ERC grant, my group has identified a mechanism by which protein aggregates associated with diverse neurogenerative diseases enter cells. My lab also has identified powerful strategies to help cells survive with misfolded proteins, a hallmark of neurodegenerative diseases. In mice, this approach reduces several neurodegenerative diseases. Our work demonstrates that generic approaches aimed at helping cells to survive lethal accumulation of misfolded proteins can be useful to prevent the devastating neurodegenerative diseases in animal models. The small molecules we have identified selectively inhibit a regulatory subunit of a serine/threonine phosphatase controlling the termination of a natural defence against misfolded proteins, an interesting finding because phosphatases were previously thought to be undruggable. We have expanded on this idea and developed assays to selectively inhibit regulatory subunits of phosphatases. The assays are versatile and in principle, generically applicable to any phosphatases. This work has broad relevance because there are hundreds of phosphatases that could be inhibited using the same paradigm consisting of targeting their regulatory subunits. This opens up a broad range of possibilities to manipulate cellular function for therapeutic benefit. A summary of this work can be seen on https://www.ibiology.org/speakers/anne-bertolotti/.
