The goal of our lab is to understand how signal transduction is disrupted to cause intellectual disability, which is a major healthcare challenge world-wide. Recent data indicates that genes encoding signalling enzymes such as protein kinases are frequently mutated in intellectual disability, suggesting that these components may form novel signalling pathways which are required for neurological functioning and are disrupted in patients (1). We recently discovered the first example of such a pathway, comprising Ser-Arg Protein Kinase (SRPK)(2) and the RNF12/RLIM E3 ubiquitin ligase (3,4), which controls neurodevelopmental processes and is disrupted by intellectual diability gene variants (5,6).

This PhD project aims to map signalling pathways that are disrupted in intellectual disability, with the overarching goal of uncovering much-needed therapeutic opportunities in this area. The successful candidate will have the opportunity to utilise exciting new tools and reagents in the lab and expand on our recent progress in dissecting intellectual disability signalling networks. Potential approaches include (phospho)proteomic profiling mass-spectrometry, modelling human neural development using pluripotent stem cells, animal models of intellectual disability, cutting edge biochemistry, and structural analysis using Cryogenic Electron Microscopy (CryoEM). The student will be embedded in a dynamic team with a track record in dissecting intellectual disability signalling networks. They will also have excellent opportunities for further internal and external collaborations with leading experts in this area.

References

1) Therapeutic validation and targeting of signalling networks that are dysregulated in intellectual disability. Bustos & Findlay, FEBS J. 2023 Mar;290(6):1454-1460. doi: 10.1111/febs.16411. PMID: 35212144

2) Functional Diversification of SRSF Protein Kinase to Control Ubiquitin-Dependent Neurodevelopmental Signaling. Bustos et al Dev Cell. 2020 Dec 7;55(5):629-647.e7. doi: 10.1016/j.devcel.2020.09.025. PMID: 33080171

3) RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation. Bustos et al, Cell Rep. 2018 May 8;23(6):1599-1611. doi: 10.1016/j.celrep.2018.04.022. PMID: 29742418

4) An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations. Segarra-Fas et al, Sci Signal. 2022 Jul 12;15(742):eabm5995. doi: 10.1126/scisignal.abm5995. PMID: 35857630

5) A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome. Bustos et al, Sci Rep. 2021 May 5;11(1):9560. doi: 10.1038/s41598-021-88911-3. PMID: 33953269

6) Activity-based probe profiling of RNF12 E3 ubiquitin ligase function in Tonne-Kalscheuer syndrome. Bustos et al, Life Sci Alliance. 2022 Jun 28;5(11):e202101248. doi: 10.26508/lsa.202101248. PMID: 35764390