Assessing neuronal and glia contributions to Autosomal Dominant Optic Atropy

About This Grant

Project Summary Autosomal Dominant Optic Atrophy (ADOA) is a progressive neurodegenerative disorder that particularly affects retinal ganglion cells (RGCs) and is typically diagnosed in the first decade of life. Mutations in the OPA1 gene, a nuclear gene encoding a mitochondrial protein, are responsible for most cases of ADOA. Though Opa1 is present in all cells and embryonic lethal when homozygous, patients with ADOA are heterozygotes and their symptoms are typically restricted only to progressive loss of vision due to the degeneration of retinal ganglion cells. There are presently no treatments for ADOA and a limited understanding of the pathological mechanisms. In a mouse model of ADOA we determined that there was progressive thinning of myelin in the optic nerve and loss of myelin has also been detected in post-mortem tissue from ADOA patients. This finding raises the question of how significant the change in myelin is to the subsequent pathologies. Because OPA1 mutations alter mitochondria in all cell types, it is possible that defects in the myelinating oligodendrocyte mitochondria, and not just those of the retinal ganglion cells, will contribute to axon degeneration and physiological defects. To address this question, we will use mice with a floxed allele of Opa1 that allows the selective removal of one copy of Opa1 from either retinal ganglion cells or oligodendrocytes and quantify the consequences for optic nerve myelin, axon degeneration, survival of retinal ganglion cells, and visual evoked potentials. Successful conclusion of the project will enhance our mechanistic understanding of the disorder by determining the relative contribution of neuronal vs glial loss of Opa1 and will help guide future therapeutic strategies by determining the cell type or types that need to be targeted.