The Pathological Role of Risk Genes and Ageing in Drosophila.

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Insights into the genetic origins of Alzheimer’s disease (AD) have been made through Genome Wide Association Studies (GWAS), in which the UK DRI at Cardiff University has played a major role. We aim to assess if and how these newly discovered genes contribute to several pathological features in Drosophila including: dysregulated neuro immune interactions, mitochondrial dysfunction and the accumulation of amyloid/ Tau. A particular focus of the research will be to investigate how glia contribute to synaptic loss, most correlative of cognitive decline in patients through defined in vivo phagocytosis pathways. Drosophila is an excellent system to use for this approach since many of the genes we wish to study are conserved and experiments can be conducted at a rapid and relatively inexpensive manner. Once disease modifying candidate genes are found we have a variety of tools (e.g. GCaMPs, markers for redox and live imaging of organelles) to determine precisely how neuronal physiology has been altered in vivo. The state of the art microscopy facilities purchased at the UKDRI at Cardiff are critical for this type of research. By investigating these factors in the adult fly, rather than at larval stages or in vitro, we will bypass possible developmental factors that may confound results. We can then further genetically define the intracellular pathway in which newly discovered molecules function in. For example, if an AD risk gene causes a decreased synapse engulfment when mutated/ knocked down, we can overexpress it to determine whether the phenotype can be rescued. Using this genetic interaction approach we can also determine whether AD risk genes signal in known pathways and function ‘up stream’ or ‘downstream’ of interacting molecules. Experiments in Drosophila will therefore allow us to understand the mechanisms of AD risk associated genes and their interaction with the ageing nervous system.

Specific Research streams:
1) To investigate how new risk genes discovered from GWAS approaches contribute to the pathology in AD.
2) To discover new genes which contribute to mitochondria ageing in neurons using an unbiased in vivo genetic approach and investigate them in models of AD and other dementias.