Protein quality control in health and disease

Accumulation of misfolded proteins is a defining feature of numerous diseases. My work aims to identify strategies that rescue cells from protein quality control failure with the view that such strategies may lead to generic therapies for diverse protein misfolding diseases. Recent and transformative discoveries in the lab have validated this concept. One recently discovered strategy consists of a selective inhibitor of the constitutive regulatory subunit of the eIF2α phosphatase to transiently decrease protein synthesis rates, thereby correcting folding defects by increasing protein quality control capacity. This approach is safe, novel and very promising because it may benefit common neurodegenerative diseases. This proposal aims at testing this new and exciting possibility in mouse models of common neurodegenerative diseases, reconstituting phosphatase inhibition using purified components and examining the functional consequences of the inhibitors on the translatome. We will also identify other phosphatases controlling the termination of stress signalling pathways anticipating that prolonging stress signalling could be a generic paradigm to enhance the natural cellular defence systems. This research programme will bring fundamental discoveries with a translational potential relevant to a group of devastating and so far incurable diseases.