Neurobiology of the DISC1 pathway

Bipolar affective disorder and schizophrenia are severe forms of mental illness that together affect approximately one in fifty people at some time in their life. We know very little about what goes wrong in the brains of people suffering from mental illness. However, we do know that these illnesses tend to cluster in families, pointing to genetic (inherited) factors being important in increasing risk of becoming mentally ill. We have identified two such genetic factors, genes called DISC1 and PDE4B, that are damaged in some patients diagnosed with mental illness. DISC1 and PDE4B work together to control the amount of a signalling molecule called cAMP, which is needed for many important brain functions, including some of the thought processes that are abnormal in psychiatric patients. Now we want to understand in more detail how DISC1 and PDE4B interact with other factors in brain cells to carry out essential biological tasks. This will tell us more about the effect of damage to these genes upon brain function, and how this leads to mental illness. If we can understand what happens in the brain in mental illness this work may ultimately lead to development of better ways to treat schizophrenia and bipolar affective disorder.

Bipolar affective disorder and schizophrenia 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, so named because it was identified at the breakpoint of a balanced translocation that segregates with schizophrenia, bipolar affective disorder and recurrent major depression in a large Scottish family. The translocation family is possibly unique, but multiple groups, world-wide, have tested DISC1 in patients without any chromosomal rearrangement and found positive evidence for genetic linkage and association with schizophrenia, bipolar affective disorder and schizoaffective disorder. Our understanding of the biological function of DISC1 has grown steadily. We and others have shown that DISC1 is a putative scaffold protein which interacts with multiple protein partners involved in neurodevelopment, cytoskeletal function and cell signalling. Our most recent study resulted in a dramatic change in the understanding of DISC1 function through first, our identification of phosphodiesterase 4B (PDE4B) as a candidate genetic risk factor and second, our demonstration that DISC1 interacts dynamically with PDE4B to modulate cAMP, a key neuronal signalling molecule. DISC1 is arguably now the best replicated genetic finding and the DISC1/PDE4B pathway the most promising biological pathway underpinning schizophrenia and bipolar affective disorder, and a promising target for novel drug development.

In this proposal we will address four related objectives:
1. How is expression of DISC1 regulated and what are the consequences of aberrant DISC1 expression at the cellular level?
2. What is the role of DISC1 in subcellular targeting of its binding partners?
3. What is the role of DISC1 in mitochondrial trafficking, neurite extension and synaptic activity?
4. What is the molecular nature of the interaction between DISC1 and PDE4B and how is it regulated?
At the end of this research grant we expect to have made significant inroads into the molecular basis of DISC1 regulation, how this is affected by genetic variation, where in the cell and with which DISC1 isoforms PDE4B and other proteins interact, how these interactions are affected by modulation of DISC1 expression, and the impact this has upon neural cell development and activity. We also expect to have defined and developed an assay for monitoring the molecular interaction between DISC1 and PDE4B as a key step towards a future drug development programme.