Biochemical, cell biological and proteomical characterization of dysfunctional and posttranslationally modified DISC1 protein
Final Report Abstract
Disrupted-in-schizophrenia 1 (DISC1) has been established as a major gene for behavioral control involved in human mental illness and animal behavior. In this project, we have investigated the protein pathology of DISC1 to more detail by biochemical and cell biological methods and characterized the conditions which cause DISC1 to form insoluble protein aggregates and the cellular consequences they elicit. A role of DISC1 aggregates in the regulation of dopamine in vitro and in vivo was defined. The ability of DISC1 aggregates to profoundly change interactions of protein networks that include other mental illness candidates like dysbindin, CRMP1, or neuregulin 1 was demonstrated. This research has led to the definition of an extended DISC1 signaling pathway where several mental illenss candidate genes/protein converge and linked this pathway directly to a key symptom of many mental illnesses, a dysfunctional dopamine homeostasis.
Publications
- (2010). Disrupted-in-Schizophrenia-1 expression is regulated by BACE1-Neuregulin cascade. Proceedings of the National Academy of Sciences USA, 107: 5622-27
Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano SI, Hayashi-Takagi A, Stanco A, Rao S, Ishikuza K, Wong P, Korth C, Anton ES, Sawa A
- Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cellinvasive DISC1 aggresomes. (2011) Biological Psychiatry 70:604-10. Ziskind-Somerfeld Award for best publication 2011 by the Society of Biological Psychiatry
Ottis P, Bader V, Trossbach S, Kretzschmar H, Michel M, Leliveld SR, Korth C
- (2012) Generation, purification and characterization of cell-invasive DISC1 protein species. Journal of Visualized Experiments, (66), e4132
Bader V, Ottis P, Pum M, Huston JP, Korth C.
(See online at https://doi.org/10.3791/4132) - (2012) Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits. Human Molecular Genetics 21:4406-18
Bader V, Tomppo L, Trossbach SV, Bradshaw NJ, Prikulis I, Leliveld SR, Lin CY, Ishizuka K, Sawa A, Ramos A, Rosa I, García A, Requena JR, Hipolito M, Rai N, Nwulia E, Henning U, Ferrea S, Luckhaus C, Ekelund J, Veijola J, Järvelin MR, Hennah W, Korth C
(See online at https://doi.org/10.1093/hmg/dds273)
