Objective My long-term goal is 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).(i) We have recently discovered that mutant SOD1 aggregates, associated with amyotrophic lateral sclerosis, penetrate inside cells and replicate their misfolded state indefinitely, just like prions. Using our robust cell-based system, we will identify the mechanisms underlying the prion-like propagation of misfolded proteins using unbiased biochemical approaches combined with siRNA screens (Aim 1).(ii) We have discovered a novel and selective way to rescue cells from protein misfolding stress. We have identified a small molecule, guanabenz, which binds to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the alpha subunit of translation initiation factor 2 (eIF2 alpha). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolongs eIF2 alpha phosphorylation in stressed cells, thereby adjusting the protein production rates to levels manageable by available chaperones. This favors protein folding and thereby rescues cells from protein misfolding stress. This suggests that inhibition of PPP1R15A could ameliorate protein misfolding diseases. We will test this attractive possibility (Aim 2).Having provided the proof of principle that serine/threonine phosphatases are drug targets, we aim to investigate the detailed molecular mechanism by which guanabenz selectively inhibits PPP1R15A/GADD34, using a combination of biophysical and structural approaches (Aim 3). In addition, we will develop assays to identify other selective serine/threonine phosphatase inhibitors (Aim 4).Ultimately, the knowledge emanating from our work will serve to ameliorate human health and disease. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein foldingmedical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-SG-LS3 - ERC Starting Grant - Cellular and Developmental Biology Call for proposal ERC-2012-StG_20111109 See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution UNITED KINGDOM RESEARCH AND INNOVATION EU contribution € 1 431 408,00 Address POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon United Kingdom See on map Region South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Activity type Research Organisations Administrative Contact Lisa Fields (Mrs.) Principal investigator Anne Bertolotti (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNITED KINGDOM RESEARCH AND INNOVATION United Kingdom EU contribution € 1 431 408,00 Address POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon See on map Region South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Activity type Research Organisations Administrative Contact Lisa Fields (Mrs.) Principal investigator Anne Bertolotti (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data MEDICAL RESEARCH COUNCIL Participation ended United Kingdom EU contribution No data Address 20 Park Crescent W1B 1AL LONDON See on map Activity type Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Administrative Contact Lisa Fields (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data