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

被引:0
|
作者
Nitta, Yohei [1 ]
Osaka, Jiro [1 ,2 ]
Maki, Ryuto [2 ]
Hakeda-Suzuki, Satoko [2 ,3 ]
Suzuki, Emiko [4 ,5 ]
Ueki, Satoshi [6 ]
Suzuki, Takashi [2 ]
Sugie, Atsushi [1 ]
机构
[1] Niigata Univ, Brain Res Inst, Niigata, Japan
[2] Tokyo Inst Technol, Sch Life Sci & Technol, Yokohama, Japan
[3] Yokohama Natl Univ, Res Initiat & Promot Org, Yokohama, Japan
[4] Tokyo Metropolitan Univ, Grad Sch Sci, Dept Biol Sci, Hachioji, Japan
[5] Natl Inst Genet, Dept Gene Funct & Phenom, Mishima, Japan
[6] Niigata Univ, Grad Sch Med & Dent Sci, Div Ophthalmol & Visual Sci, Niigata, Japan
来源
ELIFE | 2024年 / 12卷
基金
日本学术振兴会;
关键词
dominant optic atrophy; Drosophila; OPA1; axonal degeneration; DYNAMIN-RELATED PROTEIN; SCLEROSIS-LIKE DISORDER; MITOCHONDRIAL-DNA; MUTATIONS; DISEASE; REPLICATION; FUSION; GENES; MOUSE; PATHOGENICITY;
D O I
10.7554/eLife.87880
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:25
相关论文
共 50 条
  • [1] New insights into OPA1 autosomal dominant optic atrophy
    Whitehead, Michael
    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2023, 64 (08)
  • [2] Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy
    Votruba, M
    Thiselton, D
    Bhattacharya, SS
    BRITISH JOURNAL OF OPHTHALMOLOGY, 2003, 87 (01) : 48 - 53
  • [3] A novel OPA1 mutation in a family with autosomal dominant optic atrophy
    Federico, A
    Cardaioli, E
    Gallus, GN
    Malfatti, E
    Da Pozzo, P
    Franceschini, R
    Caporossi, A
    Dotti, MT
    JOURNAL OF THE NEUROLOGICAL SCIENCES, 2005, 238 : S152 - S152
  • [4] Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy
    Fuhrmann, N.
    Alavi, M. V.
    Bitoun, P.
    Woernle, S.
    Auburger, G.
    Leo-Kottler, B.
    Yu-Wai-Man, P.
    Chinnery, P.
    Wissinger, B.
    JOURNAL OF MEDICAL GENETICS, 2009, 46 (02) : 136 - 144
  • [5] A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy
    Zhang, Juanjuan
    Yuan, Yimin
    Lin, Bing
    Feng, Hao
    Li, Yan
    Dai, Xianning
    Zhou, Huihui
    Dong, Xujie
    Liu, Xiao-Ling
    Guan, Min-Xin
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2012, 419 (04) : 670 - 675
  • [6] Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy
    Almind, Gitte J.
    Gronskov, Karen
    Milea, Dan
    Larsen, Michael
    Brondum-Nielsen, Karen
    Ek, Jakob
    BMC MEDICAL GENETICS, 2011, 12
  • [7] Autosomal dominant optic atrophy:: Penetrance and expressivity in patients with OPA1 mutations
    Cohn, Amn C.
    Toomes, Carmel
    Potter, Catherine
    Towns, Katherine V.
    Hewitt, Alex W.
    Inglehearn, Chris F.
    Craig, Jamie E.
    Mackey, David A.
    AMERICAN JOURNAL OF OPHTHALMOLOGY, 2007, 143 (04) : 656 - 662
  • [8] OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy
    Han, J
    Thompson-Lowrey, AJ
    Reiss, A
    Mayorov, V
    Jlia, H
    Biousse, V
    Newman, NJ
    Brown, MD
    GENETICS IN MEDICINE, 2006, 8 (04) : 217 - 225
  • [9] Subtle neurological and metabolic abnormalities in an Opa1 mouse model of autosomal dominant optic atrophy
    Alavi, Marcel V.
    Fuhrmann, Nico
    Nguyen, Huu Phuc
    Yu-Wai-Man, Patrick
    Heiduschka, Peter
    Chinnery, Patrick F.
    Wissinger, Bernd
    EXPERIMENTAL NEUROLOGY, 2009, 220 (02) : 404 - 409
  • [10] OPA1, associated with autosomal dominant optic atrophy, is widely expressed in the human brain
    Bette, S
    Schlaszus, H
    Wissinger, B
    Meyermann, R
    Mittelbronn, M
    ACTA NEUROPATHOLOGICA, 2005, 109 (04) : 393 - 399