Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.774003
Title: Neurodegenerative tauopathies disrupt neuronal function and circadian behaviour in Drosophila
Author: Jaciuch, David
ISNI:       0000 0004 7961 2359
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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Abstract:
Tauopathies are progressive neurodegenerative diseases characterised by the aggregation of hyperphosphorylated tau protein into neurofibrillary tangles (NFTs). To date, the majority of research has focused on NFT formation and neuronal death. However, mounting evidence suggests that clinical symptoms precede aggregate formation and cell loss. Thus, a period of cellular dysfunction precedes cell death. For further understanding, robust animal models of tau-mediated neuronal dysfunction are urgently required. In this thesis, I successfully model the early stages of tauopathies in Drosophila. First, I show tau-mediated neuronal dysfunction (progressive loss of the ERG response and abnormal visual behaviour in the flight simulator system) and neuronal death (progressive loss of the photoreceptor rhabdomeres) are temporally separable in a Drosophila eye model. I demonstrate isoform-specific effects of different 4r tau proteins in my model. For example, lGMR > 2n4r tau, but not lGMR > 0n4r tau, expression causes age-related progressive structural degeneration. I further suggest a role for PAR1 phosphorylation in tau-mediated neuronal dysfunction and show Aβ42 potently exacerbates tau-mediated neuronal dysfunction. Circadian rhythm disruption is common in tauopathies, such as Alzheimer's disease (AD). I show Drosophila expressing human tau, recapitulate many of the features of circadian dysfunction found in AD, including elevated night-time activity, gains in daytime sleep and night-time sleep loss and in LD, and progressive behavioural arrhythmicity in DD. I show that distinct subsets of clock neurons mediate different tau-evoked circadian rhythm disturbances. Tau expression in the PDF neurons, which are considered to be the master pacemaker, prolongs the free-running period and causes hyperactivity, but is insufficient to induce progressive behavioural arrhythmia in DD. All clock neurons is the most clock-restricted domain required to produce behavioural arrhythmicity. The tau species and extent of tau expression affects the circadian behavioural deficits. I find no loss of PDF neurons in flies expressing tau in the clock system. Taken together, these results show in independent neuronal populations tau-mediated neuronal dysfunction is separable from neuronal death. Collectively, these results suggest circadian dysfunction in AD is not due to neuronal death in the master pacemaker, but neuronal dysfunction throughout the clock system. In this thesis, I present parallel studies that provide a platform for the future dissection of the mechanisms underlying progressive functional and structural degeneration, which bring about clinical symptoms in the early stages of tauopathies.
Supervisor: Juusola, Mikko Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.774003  DOI: Not available
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