Molecular mechanism of schizophrenia with reference to disrupted-in-schizophrenia 1 (DISC1).

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1:1) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To elucidate how DISC1 confers susceptibility to psychiatric disorders, identification of the molecules, which bind to the domain close to the translocation breakpoint in the DISC1 gene, was performed and fasciculation and elongation protein zeta-1 (Fez1), a novel DISC1-interacting protein, termed DISC1-binding zinc-finger protein (DBZ) and Kendrin were identified. The DISC1-Fez1 interaction is up-regulated by nerve growth factor (NGF) and involved in neurite extension. Transient dissociation of the DISC1-DBZ interaction by pituitary adenylate cyclase-activating polypeptide (PACAP) causes neurite extension. Furthermore, single-nucleotide polymorphisms association studies in a Japanese population have shown the relation of the Fez1, PACAP and PACAP receptor (PAC1) genes to schizophrenia. In schizophrenia with DISC1 translocation carrier, the DISC1-Fez1 and DISC1-DBZ interaction is disrupted, and it is likely that neural circuit formation remains immature, suggesting that schizophrenia is a neurodevelopmental disease. On the other hand, the DISC1-Kendrin interaction is suggested to be involved in microtubule network formation and an association between single-nucleotide polymorphisms of the Kendrin gene and bipolar disease has also been suggested in a Japanese population. This demonstrates that a part of bipolar disease is also a neurodevelopmental disorder.