Title: Investigating neurodegeneration in a Drosophila model of tauopathy
Abstract:Axonal degeneration occurring in disease is thought to be similar to that occurring after acute injury, known as Wallerian degeneration. Wallerian degeneration is an active process that can be delayed...Axonal degeneration occurring in disease is thought to be similar to that occurring after acute injury, known as Wallerian degeneration. Wallerian degeneration is an active process that can be delayed by the expression of the slow Wallerian degeneration (WldS) protein. In this project I sought to investigate whether WldS could delay axonal degeneration in a model of neurodegenerative disease: tauopathy. Tauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau. Using Drosophila co-expressing htau0N3R and WldS, neuronal dysfunction was investigated in larvae. However, WldS did not improve tau-mediated deficits in axonal transport, synaptic alterations and locomotor behaviour, indicating WldS does not improve tau-mediated neuronal dysfunction. Furthermore, co-expression in the adult system, in which both neuronal dysfunction and degeneration occur, did not improve locomotor behaviour nor delay the onset or slow the progression of axonal swellings indicative of axonal degeneration. A significant increase in lifespan was observed, however as this was not accompanied by delayed axonal degeneration this is likely to be an off target effect. The failure of WldS to delay tau-mediated axonal degeneration suggests that a different mechanism controls axonal degeneration in disease than in injury. Supporting this, following axotomy htau0N3R;WldS axons displayed robust protection on a par with WldS axons. Interestingly, subsequent bystander protection against tau-mediated axonal swellings was observed in injured htau0N3R;WldS axons. This further supports that different mechanisms control axonal degeneration in chronic disease and acute injury. Mitochondria play an important role in neuronal dysfunction and degeneration in tauopathy, but how this contributes to axonal degeneration remains unclear. Expression of htau0N3R results in mitochondrial mislocalisation in the larval model of neuronal dysfunction. Restabilising the microtubule cytoskeleton using the drug NAP restored axonal transport but did not rescue mitochondrial mislocalisation, indicating that the mislocalisation is not simply due to the loss microtubule stabilisation by tau.Read More
Publication Year: 2015
Publication Date: 2015-06-01
Language: en
Type: dissertation
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