
ショウジョウバエのOPA1遺伝子欠損は、ヒトの自動優性視神経萎縮症の病理を模倣し、ヒトOPA1遺伝子の発現によりその変性が部分的に回復する。さらに、ヒトOPA1遺伝子の特定の変異は、この回復を抑制することで、機能低下型と優性阻害型の変異を区別できる。


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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 like GTPase ( OPA1 ) gene. OPA1 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 dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 ( hOPA1 ) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, mutations previously identified did not ameliorate the dOPA1 deficiency phenotype. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant negative mutations in hOPA1 . This fly model aids in distinguishing DOA from DOA plus and guides initial hOPA1 mutation treatment strategies.

### Competing Interest Statement

The authors have declared no competing interest.

Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

自動優性視神経萎縮症の病理学的意義を明らかにするためのショウジョウバエモデル