DISC1 complex: Neurosignalling and genetics

Bipolar affective disorder and schizophrenia are severe and debilitating forms of mental illness that together affect up to one in fifty persons at some point in their life. These illnesses tend to cluster in families. This and other evidence points to genetic (inherited) factors being important. Recently, we identified one such factor, called Disrupted in Schizophrenia 1, or DISC1 for short. There is now a lot of support from many studies for this being an important risk factor not just in schizophrenia, but also bipolar disorder and depression. Recently, we identified another risk factor gene called PDE4B. PDE4B was already thought to be important in building memories in the brain. It does so by regulating the amount of a molecule called cAMP, the level of which is key to many brain processes. It turns out that DISC1 acts as a kind of master organiser not just of PDE4 but also other proteins that are believed to be important for how the brain develops, and processes sensory information. Our research is aimed at understanding these complex processes in more detail, to understand what makes them go wrong in persons with mental illness, with the long term hope that this knowledge and understanding may bring us closer to better treatments for these devastating illnesses. In the process, we also expect to reach a fuller understanding of how the brain normally develops, and of how the mind works.

Schizophrenia (SZ) and Bipolar disorder (BP) are both in the WHO top ten estimates for disease related lifetime disability. Jointly, they have a lifetime incidence of about 2%. Both have strong genetic components, but until recently few genetic findings were consistently replicated. In 2000, we positionally cloned a completely novel gene, Disrupted in Schizophrenia 1, identified at one breakpoint of a balanced translocation that segregates with schizophrenia, bipolar affective disorder and recurrent major depression in a large Scottish family. Growing evidence from a wide range of study designs (linkage, association, and gene resequencing) finds broad support to link genetic variation in DISC1 to risk of SZ, BP and related major mental illness. The importance of DISC1 is further supported by the strong emerging evidence for the biological function of DISC1. DISC1 is a scaffold protein which interacts with multiple protein partners involved in neurodevelopment, cytoskeletal function and cell signalling. In 2005, we demonstrated that DISC1 interacts dynamically with phosphodiesterase 4B (PDE4B) to modulate cAMP, a key neuronal signalling molecule. We and others have early, but persuasive evidence for a role of DISC1 at the centrosome, at the synapse and in neurogenesis. A core complex of the proteins DISC1/PDE4/NDEL1/NDE1 is likely to be involved in these processes, each of which has an independent or co-dependent effect of genetic risk. Thus, the DISC1 complex is arguably the most promising biological pathway underpinning SZ and BP, a promising target for novel drug development and a route to understanding key aspects of brain development, learning and memory.

In this proposal we will address two inter-related questions:
1)What defines the DISC1 complex and how is it regulated?
2)How does the DISC1 complex impact on neurosignalling?
These two objectives will be integrated and informed by a third cross-cutting theme:
3)What is the effect of pathogenic mutations on DISC1 complex function?

To this end, we will build upon our now extensive biological resources, assays and techniques to test our hypotheses in cultured cells and primary neurons derived from normal and DISC1 mutant mouse models. At the end of this research grant we expect to have made significant inroads into the overarching question of the nature, regulation and function of the DISC1 complex and the impact of genetic variation.