Atkin, T.A.; (2011) Investigating the role of Disrupted-in-Schizophrenia 1 in neuronal function and disease. Doctoral thesis , UCL (University College London).

Abstract

Disrupted In Schizophrenia-1 (DISC1) is a key susceptibility gene implicated in schizophrenia. Previous studies have revealed a potential role for DISC1 in kinesin-1 mediated transport, the same motor responsible for powering mitochondrial transport. Mitochondria are highly dynamic organelles that must be correctly transported to neuronal regions with high energy demand such as growth cones and pre and postsynaptic domains. Disruption of mitochondrial transport impairs correct neuronal development, synaptogenesis and synaptic function. This work demonstrates that DISC1 regulates the level of mitochondrial transport in neurons. Furthermore, DISC1 mediated effects on mitochondrial transport are compromised by a disease associated single nucleotide polymorphism in DISC1, demonstrating a novel role for DISC1 is the brain, and suggesting synaptic energy loss as a potential mechanism explaining DISC1’s contribution in disease. Further investigation of the underlying mechanism revealed a key role for the GSK3β signalling pathway in the regulation of DISC1 mediated control of mitochondrial transport. A further disease mechanism of DISC1 is also addressed. DISC1 forms insoluble protein aggregates in vitro and in human post-mortem brain tissue, but the cellular dynamics of these DISC1 aggregates and their effects on neuronal function are unknown. Via characterisation of DISC1 protein aggregates, these findings localise aggregates to the aggresome, demonstrate a compromised exchange between DISC1 in the aggresome and the cytosolic pool and show a loss of functional DISC1 from the cytosol. Finally a pathological effect of DISC1 aggresome formation in neurons is identified, as aggresome containing neurons display disrupted intracellular transport of mitochondria. Findings presented in this work therefore show a functional role of DISC1 in mitochondrial transport, investigate the mechanisms by which DISC1 mediates this, and finally show the existence of aggresomal DISC1 with disruptive effects on neuronal function, therefore suggesting a novel DISC1 based mechanism for the neuronal contribution to schizophrenia.

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