DISC1 is the product of a gene that is truncated in members of a Scottish large family as a consequence of a balanced translocation (discovered by partner 6); Carriers of the truncated DISC1 have an extraordinarily high prevalence of SCZ and other forms of CMI. This establishes DISC1 as the first gene product with a direct, causal role in the development of CMI. It has therefore been argued that DISC1 might be used as a “molecular Rosetta stone” to unveil the molecular mechanisms leading to CMI, just as mutations in the rare genes encoding amyloid precursor protein (APP) or the presenilins have been successfully used to resolve the molecular mechanisms of Alzheimer’ s disease (AD).
The DISC1 gene is currently the best-characterized gene associated with behavioural phenotypes in humans and animals with numerous genetic association studies, backing up the original linkage study in the Scottish pedigree. Eight transgenic animal models expressing mutant DISC1 constructs displaying behavioural and anatomical phenotypes associated with SCZ support a key role of DISC1 in behavioural control. On top of this, several major signal transduction pathways have been linked to DISC1, including the PDE4B/cAMP and GSK-3 pathways and many more protein-protein interactions are known.
In this respect, it is conceivable that DISC1 partners or routes downstream of it might be the relevant culprits in non-genetic CMI cases although there is evidence showing that DISC1 itself plays a key role. Thus, the study of the structure, functions, partners and routes of the DISC1 pathway will provide essential keys on the molecular mechanisms underlying CMI.
The scientific objectives of IN-SENS are:
- Further delineate and explore the extended DISC1 pathway, identify additional members, and its cellular biology / pathology (Research Team 1)
- Translate impairment of the extended DISC1 pathway into animal models and demonstrate the functional significance (Research Team 2)
- Translate impairments of the DISC1 pathway in diagnostics and genetics (Research Team 3)
- Translate impairment of the extended DISC1 pathway into the clinical psychiatric practice (Research Team 4)