Our lab has received funding from the MRC to carry out single cell sequencing of brains of fly models of C9orf72 hexonucleotide (C4G2) repeat expansion toxicity. The mutation in the C9orf72 gene with a hexanucleotide repeat has been reported multiple times to be the most common genetic cause of FTD and ALS (Frontotemporal Dementia and Amyotrophic Lateral Sclerosis), both of which are devastating neurodegenerative diseases having no cures currently. Our lab previously created fruit fly models expressing 36(C4G2) repeats, these are highly toxic to adult neurons of fruit flies. This is one of the most commonly used fly models of disease.

FTD and ALS, like many neurodegenerative diseases, display selective neuronal vulnerability: only some neuronal population succumb to disease, even though the toxic species are ubiquitously expressed. Our lab proposes to identify which neuronal populations are selectively depleted in response to expression of the repeats and analyse which pathways are activated in vulnerable and resistant neuronal population using our fly model of disease. This will be done by scRNA sequencing across multiple timepoints, tracking disease development. Identified pathways will be validated in mouse models of disease in collaboration with Adrian Isaacs at the Dementia Research Institute at UCL.