RRC ID 81475
Author Nitta Y, Osaka J, Maki R, Hakeda-Suzuki S, Suzuki E, Ueki S, Suzuki T, Sugie A.
Title Drosophila model to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy.
Journal Elife
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 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.
Volume 12
Published 2024-8-23
DOI 10.7554/eLife.87880
PII 87880
PMID 39177028
PMC PMC11343565
MeSH Animals Disease Models, Animal* Drosophila / genetics Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Drosophila melanogaster / genetics Drosophila melanogaster / metabolism GTP Phosphohydrolases* / genetics GTP Phosphohydrolases* / metabolism Humans Membrane Proteins Mutation Optic Atrophy, Autosomal Dominant* / genetics Optic Atrophy, Autosomal Dominant* / metabolism Optic Atrophy, Autosomal Dominant* / pathology
Resource
Drosophila DGRC#101231 DGRC#101878 DGRC#111438