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DUY H. NGUYEN, Keun-Young Kim, Guy A. Perkins, Marcel V. Alavi, Robert N. Weinreb, Won-Kyu Ju; OPA1 Mutation Induces NMDA Receptor Activation, Mitochondrial Fission and RGC Death in the Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2367.
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OPA1 mutation is associated with autosomal dominant optic atrophy (ADOA) in humans. Although heterozygous Opa1enu/+ mice have increased retinal ganglion cell (RGC) loss and optic nerve degeneration, the pathological mechanism of RGC death remains unknown. The goal of this study is to determine whether reduction of OPA1 protein induces NMDA receptor activation, mitochondrial fission, and RGC death in Opa1enu/+ mouse retina.
Heterozygous Opa1enu/+ mice, with a mutation that leads to reduced OPA1 expression, were genotyped, and the cellular distribution and expression for OPA1, GFAP, Iba1 and NMDA receptors (NR1, NR2A, and NR2B) were assessed by immunohistochemistry or Western blot. Mitochondrial structural changes were assessed by conventional electron microscopy (EM) and 3D electron tomography. RGC death was quantified using FluoroGold labeling. Bax and phospho-Bad expression were measured by qPCR, immunohistochemistry, or Western blot.
Heterozygous Opa1enu/+ mice showed significantly increased RGC loss at 9 months old, as well as activated astroglia and microglia in the ganglion cell layer (GCL) compared to controls. Further, these OPA1-mutant mice had significantly increased expressions of NMDA receptors (NR1, NR2A, and NR2B), and increased immunoreactivities for these receptors in the GCL. EM analysis revealed mitochondrial fission in the axons of the optic nerve heads of Opa1enu/+ mice. Bax gene and protein expression were significantly increased in the retina of Opa1enu/+ mice compared to control mice. In contrast, Opa1enu/+ mice showed a significant decrease of phospho-Bad protein expression in the retina.
These results suggest that NMDA receptor activation-mediated mitochondrial dysfunction may be an important mechanism in RGC death of heterozygous Opa1enu/+ mice.
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