The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice
-
Published:2024-02-09
Issue:1
Volume:81
Page:
-
ISSN:1420-682X
-
Container-title:Cellular and Molecular Life Sciences
-
language:en
-
Short-container-title:Cell. Mol. Life Sci.
Author:
Affortit Corentin, Coyat Carolanne, Saidia Anissa Rym, Ceccato Jean-Charles, Charif Majida, Sarzi Emmanuelle, Flamant Frédéric, Guyot Romain, Cazevieille Chantal, Puel Jean-Luc, Lenaers Guy, Wang JingORCID
Abstract
AbstractDominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.
Funder
Fondation de l'Avenir pour la Recherche Médicale Appliquée Fondation pour la Recherche Médicale Fondation des Gueules Cassées Labex EpiGenMed
Publisher
Springer Science and Business Media LLC
Reference90 articles.
1. Johnston PB, Gaster RN, Smith VC, Tripathi RC (1979) A clinicopathologic study of autosomal dominant optic atrophy. Am J Ophthalmol 88:868–875. https://doi.org/10.1016/0002-9394(79)90565-8 2. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26:211–215. https://doi.org/10.1038/79944 3. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210. https://doi.org/10.1038/79936 4. Lenaers G, Neutzner A, Le Dantec Y, Juschke C, Xiao T, Decembrini S, Swirski S, Kieninger S, Agca C, Kim US, Reynier P, Yu-Wai-Man P, Neidhardt J, Wissinger B (2020) Dominant optic atrophy: culprit mitochondria in the optic nerve. Prog Retin Eye Res. https://doi.org/10.1016/j.preteyeres.2020.100935 5. Amati-Bonneau P, Guichet A, Olichon A, Chevrollier A, Viala F, Miot S, Ayuso C, Odent S, Arrouet C, Verny C, Calmels MN, Simard G, Belenguer P, Wang J, Puel JL, Hamel C, Malthiery Y, Bonneau D, Lenaers G, Reynier P (2005) OPA1 R445H mutation in optic atrophy associated with sensorineural deafness. Ann Neurol 58:958–963. https://doi.org/10.1002/ana.20681
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|