Understanding the modifiers of dysregulated RNA metabolism in ALS/FTD

Many genetic mutations that perturb RNA-binding proteins (RBPs) can cause amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (ALS-FTD), but their effects are seemingly buffered against for several decades before symptom onset. My proposal aims to identify and characterise the ‘adaptive’ pathways that modify the impact of mutations through direct interactions with relevant ribonucleoprotein complexes (RNPs), thereby buffering the dysregulated RNA metabolism. I will leverage my skills in iPSC-based model creation, disease modelling and phenotypic screening with the systems biology expertise of the Ule lab to: a) establish three separate degron-based iPSC-derived models that enable precisely timed initiation and reversal of mutant RBP expression; b) investigate changes in RNA metabolism and RNP assembly at precise time points upon induction and reversal of mutant RBP expression in iPSC-derived neurons; c) establish bichromatic molecular sensors under control of deregulated RNA events to screen for genetic modifiers and assess their capacity to buffer RNA dysregulation; and d) explore the convergent mechanisms by which modifiers buffer RNA dysregulation by studying protein-RNA and RNA-RNA contacts to unravel the higher-order organisation of RNP condensates. Collectively I aim to disentangle the mechanisms that directly buffer the impact of various ALS/FTD-causing mutations in RBPs to maintain physiological homeostasis.