Generation and biochemical characterization of a transgenic rat model for sporadic mental disease by overexpressing full length DISC1

• Antragsteller: Professor Dr. Carsten Korth
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2009 bis 2012
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 153683831

DISC1 has been demonstrated to be genetically linked to familial chronic mental diseases (CMD) of mixed phenotypes, like schizophrenia or the affective disorders. The mutation causing genetic CMD has been successfully modeled by expression in several transgenic mouse lines reflecting neuropatholgoical and behavioral phenotypes of CMD. However, the majority of CMD cases are not genetic. To investigate pathomechanisms in non-mutant, full length DISC1 in sporadic cases of CMD, posttranslational modifications were analyzed. We demonstrated that a subset of cases with sporadic CMD could be characterized by the occurrence of insoluble DISC1 in brains. Insoluble DISC1 becomes dysfunctional in terms of lack of binding to NDEL1, a major ligand for executing neuronal functions. Here, we propose to generate a transgenic rat model as a model for sporadic CMD by overexpressing human full length DISC1 under the control of the prion protein promotor. The idea is that, similar to transgenic animal models of Alzheimer s and Huntington s dissease, overexpression of the disease-causing protein may lead to mutlimeric and insoluble protein species in vivo causing a clinical phenotype similar to that of the human disease. The advantages of a transgenic rat model, like better anatomical resolution for neuropathological and imaging studies, tissue sampling and more differentiated behavioral tests will be fully exploited.

• DFG-Verfahren: Sachbeihilfen