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Selective inhibition of phosphatases to boost protein quality control : A possible treatment for degenerative diseases

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The deposition of misfolded proteins is a defining feature of many age-dependent human diseases, including the increasingly prevalent neurodegenerative diseases. Why misfolding-prone proteins accumulate in aged cells remains largely unclear. Cells normally strive to ensure that proteins get correctly folded and have powerful and sophisticated protein quality control mechanisms to maintain protein homeostasis under adverse conditions. However, with age, the cellular defence systems against misfolded proteins gradually fail, leading to the accumulation of misfolded proteins with devastating consequences for cells and organisms. In principle, improving the cells’ ability to deal with misfolded proteins should represent a generic approach to reduce pathology in diverse protein misfolding diseases. My lab has identified powerful strategies to help cells survive when protein quality control fails and implemented some of these strategies in mice. Exploiting the current knowledge on protein quality control systems, we have identified a small drug-like molecule that safely boosts the natural defence system against misfolded proteins. Our work demonstrates that generic approaches aimed at helping cells to survive protein quality control failures can be useful to prevent protein misfolding diseases, including the devastating neurodegenerative diseases.

The small molecules we have identified selectively inhibit a regulatory subunit of a serine/threonine phosphatase controlling the termination of a proteostatic pathway, 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.

This talk is part of the Biophysical Seminars series.

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