Reducing the expression of Lap or Zydeco in Drosophila causes phenotypes similar to Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, affecting approximately 50 million people worldwide, resulting in the progressive loss of cognition. Although there has been some progress in determining the underlying causes of the pathology, most cases are sporadic, meaning there is an urgent requirement to identify and characterise novel genes implicit in its pathogenesis. One way in which this is achieved is through Genome-Wide and Epigenome-Wide Association Studies. These studies can identity gene loci potentially linked to the disease. However, these loci tend to lie between genes or in non-coding regions of the genome and hence the findings often result in false positives. Therefore, the use of Drosophila is integral in these studies; by using Drosophila, experiments can be performed in a cost and time efficient way to screen these. Using the GAL4/UAS system, a genetic manipulation tool in Drosophila, I expressed RNAi against Drosophila orthologs of human genes highlighted from Genome-Wide and Epigenome-Wide Association Studies, reducing their expression. I then screened through these mutants using assays set up to identify AD-like behaviour in Drosophila. RNAi expression in the eye gave a reduction in the surface area, a phenotype associated with the degeneration of photoreceptors. Zyd, encoding a potassium dependent sodium/calcium exchanger, and Lap, encoding a protein involved in vesicle formation, showed promising results in this assay, and so were chosen to be further investigated. Decreasing expression of Zyd or Lap in all neurons caused a shortened lifespan and a reduction in the climbing ability of the Drosophila. Other AD-like behaviours were observed with these flies; reduced sleep and an impairment in memory. These results are consistent with the effect displayed by human AD causal genes, Tau and Aβ42 overexpressed in Drosophila. These results demonstrate that the reduction in both Lap and Zyd has a potential link to AD pathology.

Date of Award	25 Jan 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	James J L Hodge (Supervisor) & Paul Dodson (Supervisor)