OPA1 Mutation and Retinal Ganglion Cell Degeneration

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DESCRIPTION (provided by applicant): Autosomal Dominant Optic Atrophy (DOA) is the most common hereditary form of optic neuropathy, leading to central vision loss in young children. In DOA retinal ganglion cells die and the optic nerve degenerates by an unknown mechanism. Unfortunately, there is no treatment or cure for DOA. Recent advances identified the gene that is mutated in DOA. The gene maps to chromosome 3q28 and is called Optic Atrophy Type 1 (OPA1). Intriguingly, OPA1 encodes a mitochondrial protein. The precise function of OPA1 remains unclear. However, in its yeast homologue, OPA1 may promote mitochondrial fusion and maintain the mitochondrial network and the mitochondrial DNA (mtDNA). OPA1 is a dynamin-related GTPase and may act either as a mechano-enzyme or a regulatory GTPase. The goal of this project is to identify the mechanism underlying retinal ganglion cell and optic nerve degeneration in DOA. The specific questions that will be addressed here are: (1) Do OPA1 mutations lead to breakdown of the mitochondrial network, mtDNA depletion, and abnormal mitochondrial ultrastructure? (2) Does OPA1 inactivation result in respiratory deficits, decrease in ATP, decrease in mitochondrial membrane potential, increase in free radicals, and sensitization to UV- or NMDA/NO-induced cell death? (3) What are the biophysical and structural characteristics of OPA1? In this study retinal ganglion cells will be studied using "interdisciplinary" approaches including 3D imaging, electron tomography, cell biology, molecular genetics, and bioenergetics. In addition, bioinformatics and structure biology will be used to unravel the function of OPA1. This study will embark on the first detailed cellular, molecular, biochemical and structural analysis of OPA1 and its mutations. Results obtained here may reveal a mechanistic explanation for the retinal ganglion cell death in DOA. Importantly, insights gained here may set the foundation for new therapies to fight vision loss in DOA.