Protrudin and Golgi Satellites: Novel targets for axon regeneration and neuroprotection in the visual system

This proposal aims to develop gene therapy for degenerative eye disease whilst investigating the molecular mechanisms required for regeneration in the central nervous system (CNS). Our recent work demonstrated that delivering a molecule called Protrudin to the eye allowed for regeneration in the optic nerve and neuroprotection in the retina, after an injury used to model optic nerve disease.

Glaucoma is a common optic nerve degenerative disease affecting 80 million patients worldwide. It is associated with raised intraocular pressure (IOP), however IOP is relevant in as little 60% of patients (varying between countries) whilst the common pathology is progressive dysfunction and loss of optic nerve fibres (axons) and retinal ganglion cells. These are the neurons that connect the retina to the brain through their axons in the optic nerve.

Neuroprotective strategies for glaucoma are of great therapeutic need. Ocular gene therapy could be a viable approach, with its success in the clinic already demonstrated for genetic eye diseases. In the case of glaucoma, an ideal gene therapy would need to be protective, as well as capable of promoting the regeneration of lost axons.

Protrudin can provide both regenerative and protective functions, but these effects could be improved. We have identified related molecules that also stimulate regeneration or neuroprotection, and we aim to use these to synergise and amplify Protrudin's effects.

A first part of the work will evaluate Protrudin-focused gene therapies for the visual system in well-established models of optic nerve injury and retinal disease. We aim to develop gene therapy tools that would allow for Protrudin and a partner gene to be delivered in a single vector to increase efficacy and promote dual therapeutic benefit. These studies would provide pre-clinical validation of a gene therapy for treating degenerative eye disease.

Protrudin is a scaffold-type molecule that localises to the axonal endoplasmic reticulum (ER). This is a cellular organelle that extends as an extremely fine tube throughout axons. We previously found that Protrudin can stimulate regeneration by increasing the amount of ER in axons. The ER is a complex organelle. It could provide many functions that might be therapeutically useful, but we have not characterised these.

We have been studying the functions that the ER and Protrudin might be providing in axons and have discovered a potential role for an organelle called Golgi Satellites. A second part of the work will use cutting edge cell biology techniques to test a key mechanistic hypothesis: Protrudin drives axon regeneration by coordinating an axonal interaction between ER and Golgi Satellites.

We will investigate Protrudin as a linker between the axon ER and Golgi Satellites and will characterise this important machinery and its role in axon regeneration. An axonal interaction between these organelles could indicate that axons rely on more diverse cell biology than currently considered. The work will characterise the cellular machinery at this interaction site and determine its functions.

We will investigate a role for Golgi satellites in regeneration and examine whether they can also be targeted therapeutically.

This molecular research will expand the implications of the study, uncovering targets for promoting axon regeneration and neuroprotection that could have relevance in the CNS beyond visual impairment.