Characterisation of DISC1 ubiquitination and its potential as a therapeutic intervention for psychiatric disorders

Since its discovery over a decade ago, DISC1 has become one of the most promising candidate genes for Schizophrenia and associated chronic mental disorders. This notion has been supported by a wealth of evidence from genetic and biochemical studies. With multiple interacting partners, DISC1 acts as a scaffold protein, orchestrating vital signalling pathways that underpin neurodevelopment and signalling. While the aetiology of Schizophrenia is poorly understood, loss of DISC1 protein function remains one of the proposed disease mechanisms. Furthermore, its tendency to form aggregates is reminiscent of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s disease. C-terminal truncation of DISC1 (TrDISC1) is known to decrease neurite outgrowth and number in the PC12 cell line, abolish protein interaction with proteins such as Ndel1 and also disrupt vital physiological process such as mitochondrial transport. However, very little is known about the underlying disease mechanism at the molecular level. In order to gain insight in to the role of DISC1 pathway in Schizophrenia and associated mental illnesses, I studied novel post translational modifications of DISC1. The main conclusion of my thesis is that these modifications affect DISC1 turnover and its scaffold function. The work described in this thesis has uncovered 2 novel post translational modifications and identified the E3 ligase involved in regulating DISC1 turn over. My work has also laid the foundation for the design and discovery of both peptide and non-peptide, small molecule inhibitors of the DISC1 and its cognate E3 ligase interaction. These inhibitors can serve as both pharmacological tools and for further investigation of the role of this novel interaction in DISC1 pathway and the vital physiological functions it is involved in. Furthermore, this work also indicates the feasibility of controlled and directed differentiation of patient specific iPS cells in to neurons, which act as a useful tool for disease modelling