Around 1–3% of people worldwide have an intellectual disability, and many cases are caused by mutations in genes that control poorly understood signalling enzymes inside cells. This research programme aims to untangle one specific signalling pathway—called SRPK-RNF12—that the team has linked to intellectual disability. The researchers will map how this pathway goes wrong by developing new techniques to study proteins in human stem cells as they develop into neurons. They will also use structural biology to see exactly how the pathway switches on, and test its effects on brain development in both lab-grown neurons and mice. This is fundamental science. There is no immediate treatment or diagnostic tool here. But understanding the molecular wiring that fails in intellectual disability patients could eventually point to drug targets or biomarkers. Similar work on signalling pathways in other diseases—such as cancer—has led directly to therapies. If this project succeeds, it will reveal basic principles of how disrupted cell signalling derails brain development, opening a route toward future therapeutic strategies.
View original technical description
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.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know