Abstract
Neurons are particularly susceptible to mitochondrial dysfunction, due to their high energy demand, resulting in a strong association between mitochondrial dysfunction and neurodegenerative disease. Cellular changes in response to mitochondrial dysfunction are currently poorly understood and appear to change depending on the cause of the mitochondrial dysfunction. However, manipulation of pathways known to be involved in this response have reversed the effects of mitochondrial dysfunction in Drosophila and mouse models. In this thesis, I aim to further investigate the cellular response to mitochondrial dysfunction in different models of mitochondrial dysfunction and to identifying novel genes that may be useful therapeutic targets in the future.To investigate neuronal responses to different mitochondrial insults, I developed and characterised five different in vivo models of mitochondrial dysfunction in Drosophila neurons. I then evaluated transcriptional changes in these models to look for common pathways. Loss of synaptic mitochondria and overlapping transcriptional changes were observed in all five models of neuronal mitochondrial dysfunction. However, differences in ROS production and response to HIF-1α knockdown highlighted differences between the models. Manipulation of HIF-1α was beneficial in four of the models, identifying HIF signalling as a possible avenue for future translational research.
To identify novel genes involved in the cellular response to mitochondrial dysfunction, I also carried out a genetic modifier screen in the Drosophila wing. A library of 650 RNAi lines were screened and 80 genes were identified that modify the mitochondrial dysfunction phenotype. Hits were then tested in neuronal assays, to determine if they also modify mitochondrial dysfunction in neurons. I identified two components of the Ras/MAPK pathway, Yan and Pointed, as genetic modifiers of mitochondrial dysfunction. The Ras/MAPK pathway may therefore be a potential therapeutic target for diseases associated with mitochondrial dysfunction.
| Date of Award | 1 Feb 2017 |
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| Original language | English |
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| Supervisor | Joseph Bateman (Supervisor) & Clive Ballard (Supervisor) |