How does dysregulated SRPK-RNF12 signalling cause intellectual disability?

Intellectual disability is a major mental health problem that affects 1-3% of the world population and is frequently caused by mutations in genes that encode poorly-studied signalling enzymes. In this ambitious research programme, we aim to employ our expertise in signal transduction to unravel how cell signalling is disrupted in intellectual disability patients, with the goal of identifying potential therapeutic targets. We have discovered a novel paradigm for intellectual disability signalling, the SRPK-RNF12/RLIM phosphorylation/ubiquitylation pathway. To identify molecular targets of SRPK-RNF12 signalling that are dysregulated in patients, we will comprehensively map SRPK-RNF12 dependent signalling processes by developing novel phosphoproteomic pipeline in a human stem-cell model of neuronal development. We will then use cutting-edge structural biology and biochemistry to unravel how the SRPK-RNF12 pathway is activated. Finally, we will determine how dysregulated SRPK-RNF12 signalling impacts on neurodevelopment and neurological functions in human stem-cell derived neurons and a mouse model, and unravel the wider role of SRPK-RNF12 within the intellectual disability signalling landscape. In summary, this bold proposal will uncover fundamental molecular and cellular principles of how signal transduction is dysregulated in intellectual disability patients, leading to new therapeutic strategies.