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G. Lenaers, E. Sarzi, A. Benyagoub, C. Prouteau, N. Gueguen, P. Amati-Bonneau, D. Bonneau, C. P. Hamel, P. Reynier, C. Delettre; Early Characterization of a New OPA1 Mouse Model of Dominant Optic Atrophy Reveals the Pathophysiological Mechanism of Retinal Ganglion Cells Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3841.
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© ARVO (1962-2015); The Authors (2016-present)
Dominant Optic Atrophy (DOA) is an inherited mitochondrial disease, which specifically affects Retinal Ganglion Cells (RGCs), mainly caused by mutations in OPA1 gene, encoding an intra mitochondrial dynamin involved in membrane dynamics. Because of the ubiquitous and pleiotropic functions of OPA1 in mitochondria, it remains unclear which pathophysiological mechanism is responsible for the specific RGC degeneration in DOA patients.
We have constructed a new Opa1 mouse models with the c.2708delTTAG mutation in Exon27, that mimics the most frequent mutation found in patient with DOA (30% of all cases). We have analysed its visual function by performing electrophysiological measurements (Electroretinogram (ERG) and Visual Evoked Potentials (VEP)), and evaluated the pathophysiological mechanism in the retina and optic nerve by dosage of the respiration complex activities and by observation of the mitochondrial network structures by fluorescent and electron microscopy.
We show that as early as 6 months, heterozygous Opa1 animals present altered VEP, with significant delay of the "n" and "p" peaks, which get further amplified with time, whereas ERG remains unaltered. In addition, well before the abnormal visual defect, we evidenced mitochondrial respiration deficiency specifically in the retina, while this parameter remains normal in the optic nerve, brain and skeletal muscle. Finally, mitochondrial distribution and structure are also affected early in RGC soma and around the lamina cribosa, where axons become myelinated. All these observations preceded RGC degeneration.
Our work clearly proves that the primary defect in Dominant Optic Atrophy associated to OPA1 haplo-insufficiency consists in a specific alteration of the mitochondrial respiration in the retina, which then affects mitochondrial network dynamics and visual parameters, to finally jeopardize RGCs survival.
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