7 novembre 2019: Prof. Anne Bertolotti
CMU - Auditoire Alex-F. MÜLLER (A250)
Prof. Anne BERTOLOTTI
MRC Laboratory of Molecular Biology, Cambridge, UK
«Selective inhibition of phosphatases to boost protein quality control: A possible treatment for degenerative diseases»
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.
Anne Bertolotti has made seminal contributions to our current understanding of protein quality control mechanisms in cells, which represent the cellular defence systems against potentially harmful proteins. She was one of the pioneers in the discovery of mammalian unfolded protein response and more recently discovered the pathways by which cells maintain proteasome homeostasis. She has also identified mechanisms underlying the deposition of misfolded proteins in neurodegenerative diseases and contributed to a dogmatic shift in this field with the discovery that mutant SOD1 aggregates propagate indefinitely just like prions.
With the knowledge acquired on protein quality control systems, Anne Bertolotti identified strategies to boost their function and is currently exploiting them for the treatment of neurodegenerative diseases. One of the strategies consists in selective inhibition of a phosphatase, an important advance because phosphatases were thought to be undruggable.
Anne Bertolotti obtained her Ph.D. from Strasbourg University (France) working with Pierre Chambon and Laszlo Tora, and did a post doc at The Skirball Institute of Biomolecular Medicine, NYU, New York (USA). For her post-doc, she won prestigious fellowships from the Human Frontier Science Program and the European Molecular Biology Organization. She was then an INSERM Investigator from 2000 to 2006, was elected an EMBO Young Investigator in 2005, was awarded an ERC consolidator grant in 2013, became and EMBO member in 2013 and won the Hooke Medal in 2014. In 2017, she became a Fellow of the National Academy of Medical Sciences in the UK and was awarded a Wellcome Trust Investigator Award. In 2018, she won the GlaxoSmithKline Award from the Biochemical Society. She founded CAMPHOS Therapeutics in 2017. Dr Anne Bertolotti is a programme leader in the Neurobiology Division at the Medical Research Council Laboratory of Molecular Biology (LMB) since 2006.August 8, 2019
Frontiers in biomedicine