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bioRxiv · 10.1101/2020.02.14.950097

MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Models of Glaucoma

Harun-Or-Rashid, M.·Pappenhagen, N.·Zubricky, R.·Coughlin, L.·Jassim, A. H.·Inman, D. M.
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Abstract

Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2fl/+ mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration. HighlightsO_LILoss of MCT2 in retina compromises visual function and ATP production in optic nerve C_LIO_LIMCT2 overexpression preserves RGC soma and axon number in two glaucoma models C_LIO_LIMCT2 overexpression improves energy homeostasis in optic nerve C_LI

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Harun-Or-Rashid, M., Pappenhagen, N., Zubricky, R., Coughlin, L., Jassim, A. H., Inman, D. M.. 2020-02-15. MCT2 Overexpression Rescues Metabolic Vulnerability and Protects Retinal Ganglion Cells in Two Models of Glaucoma. https://doi.org/10.1101/2020.02.14.950097

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