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Investigating the Alzheimer's disease risk gene WWOX using Drosophila melanogaster

Clarke, Hannah 2023. Investigating the Alzheimer's disease risk gene WWOX using Drosophila melanogaster. PhD Thesis, Cardiff University.
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Mutations in many genes have been identified that may mediate the risk of developing Alzheimer’s disease (AD). Understanding how these genes relate to molecular/behavioural changes, will further our understanding of pathology. One such gene is WW-domain containing oxidoreductase (WWOX). Mutations in WWOX have been associated with neurodevelopmental and neurodegenerative diseases. However, the cell-type specific roles of WWOX and its function in the context of AD are less understood. Using Drosophila melanogaster, I investigated the effect of dWwox loss-of-function and cell-type specific manipulation on neurodevelopmental and neurodegenerative disease phenotypes. Here I show that global dWwox knockout, impaired longevity, locomotion, and seizure recovery, due to alterations in excitatory-inhibitory balance. Interestingly, dWwox loss also induced sleep fragmentation, a phenotype often witnessed in AD. To understand the cell-type specific roles, I reduced dWwox in neurons or glia separately. Unlike neuronal dWwox, that had more serve phenotypes, glial knockdown reduced lifespan but left climbing unaffected. Furthermore, neuronal, glial and clock knockdown increased sleep and decreased wakefulness, outside of circadian control. Suggesting, dWwox has strong control over homeostatic sleep. To understand the molecular changes leading to such phenotypes, I performed transcriptomics and metabolomics afterneuronal manipulation in the presence of Ab42. Here I demonstrated that dWwox knockdown (+Ab42), significantly altered pyruvate metabolism via an increase in lactate dehydrogenase (Ldh). Subsequent metabolomics confirmed an increase in LLactate levels suggesting dWwox knockdown, in the context of Ab42, leads to an aerobic glycolytic shift. Here I demonstrate that this increase is likely due to amplified activation transcription factor 4 (ATF4). Remarkably, reducing Ldh rescues Ab42 locomotion deficits, suggesting targeting this pathway may provide therapeutic hope. In conclusion, decreased neuronal Wwox in a Drosophila model of AD, significantly worsens neurodegenerative and neurodevelopmental behaviours via a shift towards aerobic glycolysis – increasing ATF4, Ldh and a subsequently raising lactate concentrations.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 5 April 2024
Last Modified: 05 Apr 2024 12:57

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