Synaptic mRNA dysregulation in Neurodevelopmental Disorders

Autism spectrum disorder (ASD) involve synaptic deficits leading to excitatory-inhibitory imbalances in cortical circuits. My proposal focuses on how disturbed synaptic RNA localisation and localised translation could act as a convergent pathophysiological mechanism across 2 mouse models with haploinsufficiency of ASD risk genes. I previously demonstrated that long 3’-UTRs of synapse-localised mRNAs are structured scaffolds which recruit RBP components of neuronal RNA granules. Notably, misexpression of longer 3’UTR isoforms has been proposed as an ASD hallmark. Therefore, I hypothesise that regulation of synaptic mRNA localisation and translation is disrupted in ASD due to aberrant 3’-UTR RNA structure and RBP binding. There are three main aims: Investigate the RNA localisation and translation signatures contributing to presynaptic deficits in 2 ASD models. Describe the regulatory code of RNA structure and RBP binding on 3’-UTRs, and at full-length and single-molecule resolution for selected presynapse-localised mRNAs encoding key proteins overlapping ASD risk (ASD-mRNAs). Monitor the precise outputs of localised translation for these ASD-mRNAs, their dysregulation in ASD and the regulatory importance of cis-elements (RNA structures and RBP binding sites) encoded on the 3’-UTR. Collectively I aim to uncover the regulatory code of synapse-localised post-transcriptional regulation and their contribution to synaptic dysfunction in disease.