| Popis: |
Disrupted in schizophrenia 1 (DISC1), located on chromosome 1, was first identified due to its disruption by a chromosomal translocation, t(1;11)(q42;q14). This translocation co-segregates with psychiatric illness in the Scottish family within which it was discovered. DISC1 is a component of the mitochondrial trafficking machinery and regulates trafficking of mitochondria in neurons, possibly implicating defective mitochondrial trafficking as a contributory factor in psychiatric illness. The product of another candidate gene for psychiatric illness, Glycogen synthase kinase 3β (GSK3β), is known to interact directly with DISC1 and has also been reported to be involved in mitochondrial trafficking. The interaction of these proteins has not been investigated in this process. The work in this thesis centres around a novel mouse model of the t(1:11) translocation. I use time-lapse imaging of live cells to show that hippocampal neurons cultured from this mouse model exhibit altered axonal mitochondrial trafficking, including reduced mitochondrial pausing. I also demonstrate that the DISC1 interactor GSK3β is a component of the mitochondrial trafficking machinery and investigate effects of the t(1:11) event upon this multi-protein complex. Finally, I demonstrate altered mitochondrial motility responses to overexpression of GSK3β in mutant neurons. Defective mitochondrial trafficking, particularly reduced pausing, could result in an altered distribution of mitochondria within neurons, leading to an impaired ability to respond to cellular conditions, such as the requirement to power synaptic vesicle release or the ion pumps that restore membrane potential following action potential generation. This could ultimately affect neuron viability, leading to brain dysfunction. My data therefore support a proposed disease mechanism whereby defective mitochondrial trafficking contributes to susceptibility to psychiatric illness in carriers of the t(1:11) translocation, and may be relevant to psychiatric illness in general. |
