About the Project
The deposition of misfolded proteins is a defining feature of many age-dependent human diseases, including the increasingly prevalent neurodegenerative diseases. Why aggregation-prone proteins accumulate in aged cells remains largely unclear. Cells normally strive to ensure that proteins get correctly folded and have powerful and sophisticated mechanisms to maintain 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 organism.
In principle, improving the cells’ ability to deal with misfolded proteins should represent a generic approach to reduce the pathology in diverse protein misfolding diseases. My lab has identified powerful strategies to improve the cells’ ability to deal with misfolded proteins and implemented one of such strategy in mice to safely prevent two unrelated neurodegenerative disease. Some of the approaches we work on shed light on fundamental cell biological processes, while others pave the way to rationale therapeutics. 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. One of the strategy consists in selective inhibition of a phosphatase, an important advance because phosphatases were thought to be undruggable.
Various projects are available, aimed at capitalizing on our pioneering discoveries on phosphatases. Available projects range from biochemistry, biophysics and crystallography, cell biology and animal models of neurodegenerative diseases. Further information about the position may be obtained from Dr Anne Bertolotti– email: [Email Address Removed]
References
Pitera, A. P., Szaruga, M., Peak‐Chew, S., Wingett, S. W. & Bertolotti, A. Cellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response. Embo J e109985 (2022) doi:10.15252/embj.2021109985.
Hodgson G., Andreeva A., and Bertolotti A. Substrate recognition determinants of human eIF2α phosphatases. Open Biol 11, 210205 (2021).
Schneider K., Nelson G. M., Watson J. L., Morf J., Dalglish M., Luh L. M., Weber A., and Bertolotti A. Protein stability buffers the cost of translation attenuation following eIF2 phosphorylation. Cell Reports, 32(11), 108154.
Krzyzosiak, A., Sigurdardottir, A., Luh, L., Carrara, M., Das, I., Schneider, K., & Bertolotti, A. (2018). Target-Based Discovery of an Inhibitor of the Regulatory Phosphatase PPP1R15B. Cell. 174(5).
Carrara, M., Sigurdardottir, A., & Bertolotti, A. (2017). Decoding the selectivity of eIF2alpha holophosphatases and PPP1R15A inhibitors. Nat Struct Mol Biol, 1–13. http://doi.org/10.1038/nsmb.3443
Rousseau, A. and Bertolotti A. An evolutionarily conserved pathway controls
proteasome homeostasis. Nature. (2016). doi:10.1038/nature18943
Das, I., Krzyzosiak, A., Schneider, K., Wrabetz, L., D’Antonio, M., Barry, N., Sigurdardottir A. and Bertolotti A. (2015). Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348, 239–242.
Hanssum A., Zhong Z., Rousseau A., Krzyzosiak A., Sigurdardottir A. and Bertolotti A (2014). An inducible chaperone adapts proteasome assembly to stress. Mol. Cell. 55(4):566-77 (with front cover).
Tsaytler, P., Harding, H.P., Ron, D., and Bertolotti, A. (2011). Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science. 332, 91–94.
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