Can we repair ‘misfolding’ proteins in a common type of retinitis pigmentosa?
Research details
- Type of funding: PhD Studentship
- Grant Holder: Dr Philip Reeves
- Institute: University of Essex
- Region: South East
- Start date: October 2014
- End Date: September 2018
- Priority: Causes
- Eye Category: Inherited retinal
Overview
Retinitis pigmentosa is an inherited condition that gets worse over time, leading to blindness. It affects the light-detecting cells in the retina at the beck of the eye.
About 1 in 3 people with retinitis pigmentosa have genetic faults that affect the way a protein called rhodopsin folds into shape. Rhodopsin is a pigment that’s found in cells called ‘rods’, and this ‘misfolding’ means it can’t work normally. This triggers cell death and affects the whole retina.
The team’s previous work suggests that there is a fine balance between proteins folding correctly and misfolding. So in this project they are trying to understand more about what tips a protein over into misfolding. They are engineering versions of the rhodopsin gene with various genetic faults and seeing what types of protein each fault leads to in cells in a lab dish. They’re also looking for ways to repair the faults or make the proteins more stable. If they can find substances that are good at correcting misfolding proteins, they could then start to be developed as treatment for this type of retinitis pigmentosa.-
Scientific summary
Elucidation of molecular mechanism(s) of retinitis pigmentosa resulting from mutations in rhodopsin and development of strategies for rational intervention.
Mutations in rhodopsin account for approximately 30% of autosomal dominant retinitis pigmentosa (adRP). For the majority, a single amino acid change in the protein sequence is sufficient to bring about rod opsin malfunction and ultimately trigger the death of the rod cell. Here, the research team aims to improve understanding of the faults in these RP mutants, including autosomal recessive (ar) RP mutants, and use this information to design new approaches for therapeutic intervention. Their hypothesis is that some arRP mutants will give rise to mild defects in rod opsin folding and function, and their analysis might help us to define the threshold between normal and defective receptor formation.
The team’s previous work demonstrates that a fine balance exists between folding and misfolding in adRP mutations located in the rhodopsin N-terminus. The hypothesis is that it is the marginal stability of these proteins, exacerbated by additional N-terminal proteolytic processing of the N-terminus, which contributes to adRP. The stability and function of many of the N-terminal adRP mutants can be improved by introducing an artificial disulfide-bond.
They now aim to design a platform to enable identification of small molecule ‘correctors’ that can substitute for this engineered-in disulfide bond and stabilize the mutant apo-proteins and pigments. They also aim to define the effect of concomitant N-terminal proteolysis on the stability and function of these mutants, and to identify protease-inhibitors. Small molecule correctors of folding and stability, and protease inhibitors represent potential drugs for limiting the progression of RP resulting from mutations in rhodopsin.