Cel 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. Dziedzina nauki natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein foldingmedical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis Program(-y) 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) Temat(-y) ERC-SG-LS3 - ERC Starting Grant - Cellular and Developmental Biology Zaproszenie do składania wniosków ERC-2012-StG_20111109 Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-SG - ERC Starting Grant Instytucja przyjmująca UNITED KINGDOM RESEARCH AND INNOVATION Wkład UE € 1 431 408,00 Adres POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon Zjednoczone Królestwo Zobacz na mapie Region South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Rodzaj działalności Research Organisations Kontakt administracyjny Lisa Fields (Mrs.) Kierownik naukowy Anne Bertolotti (Dr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych Beneficjenci (2) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko UNITED KINGDOM RESEARCH AND INNOVATION Zjednoczone Królestwo Wkład UE € 1 431 408,00 Adres POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon Zobacz na mapie Region South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Rodzaj działalności Research Organisations Kontakt administracyjny Lisa Fields (Mrs.) Kierownik naukowy Anne Bertolotti (Dr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych MEDICAL RESEARCH COUNCIL Zakończenie uczestnictwa Zjednoczone Królestwo Wkład UE Brak danych Adres 20 Park Crescent W1B 1AL LONDON Zobacz na mapie Rodzaj działalności Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Kontakt administracyjny Lisa Fields (Mrs.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych