PhD in Dementia Research - Using the power of Drosophila genetics to understand Alzheimer’s disease risk gene function in the brain

Genome-wide human studies have identified genetic variances associated with increased risk of developing late-onset Alzheimer’s Disease (AD), however the precise contribution of these to pathogenesis is unknown1,2. It is often unclear what effect the genetic variance has upon expression of their surrounding genes (increase/decrease in expression) and in which cells these changes manifest in the mature brain. In vivo testing in model organisms is a robust means of assessing how changes in candidate risk gene expression may affect the ageing brain and susceptibility to AD-like pathology. The fruitfly Drosophila melanogaster presents a powerful tool in which to study the function of conserved AD risk genes in a genetically tractable in vivo model system3. Flies have a small, well-defined brain that contains a large repertoire of neuronal and glial subtypes, ideal for testing the role of risk genes in differing cell types. Their genome is readily modified, with a large toolbox of techniques available for mutating and altering gene expression.
This PhD studentship will utilize cutting edge techniques in Drosophila to assess the role of AD risk genes specifically within the ageing adult brain. The study will assess the consequence of altered AD risk gene expression in neurons and glia of ageing adult flies (transgenic, RNAi, CRISPR/Cas94). The student will test for phenotypes associated with altered risk gene expression, including behavior, electrophysiological function, neuronal/glia morphology and activity, and organization the endolysosomal, mitochondrial and autophagy machinery using advanced genetic techniques including MARCM clonal analysis5. Where appropriate, novel findings generated in these fly experiments will be further studied in mammalian and human cell lines.
The project will be hosted in the Dementia Research Institute at Cardiff University, with access to state of the art facilities and world leading experts focused on understanding the molecular biology underlying AD and other dementias.