Objetivo 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. Ámbito científico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein foldingmedical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis Programa(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) Tema(s) ERC-SG-LS3 - ERC Starting Grant - Cellular and Developmental Biology Convocatoria de propuestas ERC-2012-StG_20111109 Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-SG - ERC Starting Grant Institución de acogida UNITED KINGDOM RESEARCH AND INNOVATION Aportación de la UE € 1 431 408,00 Dirección POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon Reino Unido Ver en el mapa Región South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Tipo de actividad Research Organisations Contacto administrativo Lisa Fields (Mrs.) Investigador principal Anne Bertolotti (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (2) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo UNITED KINGDOM RESEARCH AND INNOVATION Reino Unido Aportación de la UE € 1 431 408,00 Dirección POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon Ver en el mapa Región South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Tipo de actividad Research Organisations Contacto administrativo Lisa Fields (Mrs.) Investigador principal Anne Bertolotti (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos MEDICAL RESEARCH COUNCIL La participación finalizó Reino Unido Aportación de la UE Sin datos Dirección 20 Park Crescent W1B 1AL LONDON Ver en el mapa Tipo de actividad Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Contacto administrativo Lisa Fields (Mrs.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos
