Biochemical, cell biological and proteomical characterization of dysfunctional and posttranslationally modified DISC1 protein

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DISC1 has been demonstrated to be genetically linked to familial chronic mental diseases (CMD) of mixed phenotypes, like schizophrenia or the affective disorders. While the biology of mutant DISC1 has been modeled in vitro and in vivo, a mechanism of how full length DISC1 could be dysfunctional in cases of sporadic CMD has remained elusive. The Korth lab has shown that a subset of cases with sporadic CMD can 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 further characterize the conditions under which DISC1 aggregates in cell models and to dissect the conditions under which DISC1 multimers generated in vivo and, eventually, become dysfunctional; this includes the identification of aggregation-favoring polymorphism combinations, transcripts or -degradation products, effects of cellular stressors, cytosolic dopamine, and the efect of steroid hormones. The ultimate goal is to investigate how the DISC1 protein, including when it is posttranslationally modified, is associated with behavioral and neurochemical phenotypes and, thereby, link the DISC1 protein to sporadic cases of CMD.