Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628315
Title: Investigating neuronal mitochondrial DNA loss in Drosophila melanogaster
Author: Cagin, Umut
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2013
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Abstract:
Mitochondria supply the majority of cellular ATP and have additional important roles in calcium signalling, apoptosis and lipid metabolism. Mutations in or loss of mitochondrial DNA (mtDNA) can cause neurodegeneration and has been linked to Parkinson‟s disease. However, the pathological consequences of mtDNA loss in neurons are very poorly understood. We have used the fruitfly, Drosophila melanogaster, to study how loss of mtDNA affects neuronal function. We find that both ubiquitous RNAi and overexpression of the mtDNA binding protein TFAM causes reduced mtDNA content and lethality. TFAM RNAi or overexpression specifically in motor neurons causes locomotion defects during development and age-related behavioural defects in adult flies. This demonstrates that maintenance of mtDNA is required for normal motor neuron function. In further behavioural assays we show reductions in evoked jump response, demonstrating that mtDNA loss inhibits motor neuron activity. Also, using confocal imaging we find that mtDNA loss does not cause neuronal loss or changes in synaptic bouton number during development. However, we observe a significant decrease in the number of mitochondria and the number of pre-synaptic active zones (the sites of neurotransmitter release) in motor neurons with reduced mtDNA content. Taken together these data show that neuronal mtDNA loss results in defects in synaptic development and reduced motor neuron function. We further show that these phenotypes can also result from other methods of mtDNA depletion, such as mitochondrial specific expression of the restriction enzyme XhoI. Furthermore, possible roles of TOR pathway and autophagy on motoneuron synapses were investigated. The phenotypes observed may represent the initial pathological consequences of mtDNA loss in neurodegenerative disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.628315  DOI: Not available
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