Understanding common mechanisms of repeat expansion RNA toxicity using primary and patient-derived stem cell models

Dozens of incurable neurological diseases, for which advanced age is amongst the biggest risk factors, are typified by the erroneous expansion of short repeat sequences in coding and non-coding regions of the transcriptome. In these repeat expansion disorders, expanded mutant RNA aggregates together and sequesters other biomolecules (proteins/RNA), to form microscopic RNA foci in distinct subcellular compartments. How such RNA foci contribute to neurotoxicity and whether such mechanisms are conserved across repeat expansion disorders remains poorly defined.
In work leading up to this project, the supervisory team have established models of Myotonic dystrophy (DM) and motor neuron disease (MND) - which represent two archetypal examples of RNA repeat expansion disorders. Both diseases are characterised pathologically by neuronal vulnerability. We hypothesise that this arises from as yet undescribed, but conserved mechanisms of deregulation resulting from RNA foci expression in neurons. To test this hypothesis we will define the subcellular RNA foci interactome using quantitative proteomics in mouse models of DM1 (wherein we can turn foci expression off and on) and patient-stem cell derived neurons (DM1 and MND). This will enable us to robustly define a common (and unique) foci interactome and deliver new insights into the molecular mechanisms that contribute to repeat expansion disease pathogenesis