Obiettivo In Alzheimer disease (AD) one of the key players is γ-secretase, a protease that cleaves amyloid precursor protein (APP) within its transmembrane domain to produce amyloid β (Aβ). Longer Aβ peptides have stronger tendency to aggregate, form plaques and cause inflammation - the direct causes of AD. γ-secretase activity is confined to a complex consisting of presenilin (PSEN), nicastrin (NCT), APH-1 and PEN-2. The existence of two PSEN isoforms (1&2) and several APH-1 isoforms implies heterogeneity in activities of which biological relevance is poorly understood. Preliminary findings from our laboratory indicate that the complexes containing PSEN1 and PSEN2 are differently distributed along the secretory and endocytic pathways. We hypothesize that their subcellular localization contributes to different substrate and cleavage specificity, which results in generation of Aβ peptides of different lengths.Our major objective is to examine the relationship between localization of γ-secretase isoforms and their substrates. This issue will be investigated on subcellular level, within given cellular compartments and membrane microdomains using the combination of biochemical methods with superresolution microscopy on mammalian cells. The specific objectives include identification and characterization of the sorting motifs within presenilins sequence and the sorting machinery responsible for their distinct endosomal localization. The microdomain association of PSEN1 and PSEN2 complexes will be achieved by analysis of colocalization with microdomain-specific proteins and lipid probes. A similar approach will be used to reveal different substrates of the enzymes. Finally, we will evaluate the effect of clinical PSENs mutations on the γ-secretases localization.Understanding the physiological relevance of the γ-secretase complexes and how they select their substrates may potentially contribute improving the AD models and in the long term to development of more specific drugs. Campo scientifico medical and health sciencesbasic medicineneurologydementiaalzheimernatural sciencesphysical sciencesopticsmicroscopysuper resolution microscopynatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsnatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Invito a presentare proposte FP7-PEOPLE-2012-IEF Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IEF - Intra-European Fellowships (IEF) Coordinatore VIB VZW Contributo UE € 177 000,00 Indirizzo SUZANNE TASSIERSTRAAT 1 9052 ZWIJNAARDE - GENT Belgio Mostra sulla mappa Regione Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent Tipo di attività Research Organisations Contatto amministrativo Rik Audenaert (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
