Neuronal cell cycle re-entry in ALS/FTD: protective response or neurodegeneration trigger? (360G-Wellcome-336324_Z_25_Z)

Mature post-mitotic neurons can re-enter the cell cycle, however the purpose of this newly-identified function is unknown. Furthermore, there is evidence of prolonged cell cycle re-entry in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). I hypothesise that healthy neurons deploy temporary, partial cell cycle re-entry to aid repair of damage incurred by cell stress, and that in neurodegenerative disease this response becomes maladaptive, either due to continual cell damage or regulatory mechanisms becoming dysfunctional. I will investigate this through novel application of fluorescence-based cell cycle stage reporter tools in human induced pluripotent stem cell (iPSC) derived neurons, to visualise real-time cell cycle re-entry in both health, cell stress, and models of C9ORF72 ALS/FTD: the most common genetic form of ALS/FTD. Live imaging investigation will subsequently be validated by in vitro transcriptomics and by immunofluorescence studies in human post-mortem brain tissue. Simultaneously, my proposal aims to accelerate African representation in neurodegenerative disease in vitro models. Africa has the greatest genetic diversity globally, yet it’s estimated just 3% of accessible iPSC lines are derived from individuals of African genetic ancestry. This project will generate 6 new iPSC lines derived from individuals of South African genetic ancestry and ethnicity.