<i>Drosophila</i> model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy.

Abstract

Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin <i>like</i> GTPase (<i>OPA1</i>) gene. <i>OPA1</i> encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant-negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the <i>dOPA1</i> gene in <i>Drosophila</i> can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human <i>OPA1</i> (<i>hOPA1</i>) gene, indicating that <i>hOPA1</i> is functionally interchangeable with <i>dOPA1</i> in the fly system. However, mutations previously identified did not ameliorate the <i>dOPA1</i> deficiency phenotype. By expressing both WT and DOA plus mutant <i>hOPA1</i> forms in the optic nerve of <i>dOPA1</i> mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant-negative mutations in <i>hOPA1</i>. This fly model aids in distinguishing DOA from DOA plus and guides initial <i>hOPA1</i> mutation treatment strategies.