Do secondary mitochondrial DNA defects cause retinal ganglion cell death in dominant optic atrophy?

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Dominant optic atrophy (DOA) is one of the commonest form of inherited blindness and it results in significant visual disability. DOA is caused by irreversible damage to the optic nerve, which connects the eye to the vision centres within the brain. It is a specialised cable made up of about 2 million, highly specialised cells known as retinal ganglion cells (RGCs). In 60-70% of cases, DOA is due to a mutation in the OPA1 gene but we still do not know how this genetic defect leads to disease and why only RGCs are affected. Our preliminary findings in one large family with DOA indicate that the OPA1 mutation compromises the normal function of mitochondria. Mitochondria are essential components of all human cells and they are responsible for energy production. If insufficient energy is produced, cells cannot function properly and die. To test my hypothesis further, I will analyse blood and muscle biopsies from additional families with DOA for evidence of mitochondrial dysfunction. I will also analyse RGCs from a mouse model of DOA and determine if they contain high levels of mitochondrial DNA abnormalities. Finally, I will try to identify the gene(s) responsible for DOA in those families who not carry an OPA1 mutation. RGCs are affected in other eye conditions like glaucoma and a better understanding of their selective vulnerability will help us develop more effective treatment strategies for these blinding diseases.