Prof Marcela Votruba
Telephone:+44 (0) 29 2087 0117
Fax:+44 (0)29 2087 4859
Location:Room 1.15, Maindy Road
Figure 1. Colour fundus photograph of the left optic disc showing optic nerve pallor in a patient with dominant optic atrophy and OPA1 gene mutation.
The work of my laboratory focuses on mitochondrial fusion/ fission genes and neural plasticity in human eye disease. This springs from work on the pathophysiology of inherited optic neuropathy. We are currently investigating new therapeutic targets for retinal ganglion cell loss, inner retinal degeneration and repair. We are also looking at mitochondrial shaping proteins in retinal degeneration in disease and ageing. We have been interested in the roles of fusion/ fission genes, such as Opa1 and Opa3. Opa1 is known to bind to inner mitochondrial membrane, and when mutated it is believed that the normal balance of mitochondrial fusion and fission is disturbed and programmed cell death is initiated by the loss of mitochondrial membrane potential and the release of cytochrome c. Opa3, like Opa1, is thought to have a role in mitochondrial membrane dynamics, and when mutated in the human, a complex neurodegenerative disease, comprising optic neuropathy secondary to RGC loss, cataract and neuromuscular degeneration, arises.
As part of my role as a Clinician Scientist, I also recruit patients with inherited optic neuropathy for genetic screening and I run a Retinal Clinic and a Genetic Eye Clinic, at the University Hospital of Wales.
My goals are aimed at developing a deeper understanding of inherited eye disease and ultimately utilising my position as a clinical ophthalmologist to drive the application of translational research in this area. My primary research interest is the pathophysiology of hereditary retinal and optic nerve diseases. I am currently investigating inherited optic neuropathies, which are a pure model of isolated retinal ganglion cell loss. They demonstrate a central role for mitochondria and show some progressive neurodegeneration. Retinal ganglion cells are the cells that make up the nerve of vision, taking impulses from the retina to the brain. Autosomal dominant optic atrophy is the commonest inherited optic neuropathy. It is caused by mutations in the OPA1 gene, leading to visual loss, which first starts in children and young people. Clinical understanding of the disease is poor, although we have clinical and some pathological evidence that retinal ganglion cells are deficient in the eyes of patients. There is no treatment available. Conventional clinical or research strategies have yet to make any clinical impact on this state of affairs. The mechanism of action of the mutant protein OPA1 is not known, but clues exist suggesting that the shape or function of small organelles in the cell, mitochondria, may be involved. Mitochondria are important in generating energy in the cell. Following on from our work to characterise the disease phenotype and clone the disease gene, my group has analysed the spectrum of mutations in the OPA1 gene and genotype/ phenotype correlations. We have performed functional and expression studies of the OPA1 gene and assessed its wider role in inherited optic neuropathy and we are developing model systems to explore the mechanisms and pathways of RGC loss.