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

DOI DOI DOI DOI Web Site 参考文献77件 オープンアクセス
  • Yohei Nitta
    Brain Research Institute, Niigata University
  • Jiro Osaka
    School of Life Science and Technology, Tokyo Institute of Technology
  • Ryuto Maki
    School of Life Science and Technology, Tokyo Institute of Technology
  • Satoko Hakeda-Suzuki
    School of Life Science and Technology, Tokyo Institute of Technology
  • Emiko Suzuki
    Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University
  • Satoshi Ueki
    Division of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Niigata University
  • Takashi Suzuki
    School of Life Science and Technology, Tokyo Institute of Technology
  • Atsushi Sugie
    Brain Research Institute, Niigata University

説明

<jats:p>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, we could not rescue any previously reported mutations known to cause either DOA or DOA plus. 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 . The fly model developed in this study can assist in the differential diagnosis between DOA and DOA plus and inform early treatment decisions in patients with mutations in hOPA1 . </jats:p>

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  • eLife

    eLife 12 2023-06-27

    eLife Sciences Publications, Ltd

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