AAV2-Mediated Overexpression of Monocarboxylate Transporter-2 Maintains Retinal Ganglion Cell Structure and Function During Ocular Hypertension
Denise Inman PhD Northeast Ohio Medical University, Pharmaceutical Sciences
Co-authors: Nate Pappenhagen BS Ryan Zubricky BS Assraa H Jassim BPharm Mohammad Harun-Or-Rashid PhD
Significant decreases in monocarboxylate transporters (MCTs) were observed concomitant with loss of retinal ganglion cell (RGC) function, but prior to significant RGC axon loss, in two mouse models of glaucoma. Given the important role of MCTs in moving energy substrate such as pyruvate, lactate, and β-hydroxybutyrate into neurons, we examined whether upregulating expression of the neuronal specific MCT-2 would be beneficial to RGC survival and function in two mouse models of glaucoma. For the first model, mice injected intraocularly with AAV2-GFP-MCT2 were subjected to ocular hypertension through injection of magnetic microbeads into the anterior chamber of the eye. The second model was the DBA/2J inbred strain that develops increased intraocular pressure (IOP) secondary to pigment dispersion disease. Control groups included mice injected intraocularly with AAV2-eGFP virus, with or without ocular hypertension, and the DBA/2J-Gpnmb+ strain. In mice from both glaucoma models injected with AAV2-MCT2, the virus infection led to significant increases in MCT2 protein, and significant RGC and axon protection compared to glaucoma or control virus alone. Mitochondrial and metabolic indices were improved with AAV2-MCT2 injection, including lower activation of AMPK, increased PGC-1α, and increased activity of succinate dehydrogenase and cytochrome c oxidase. These data, along with lower hexokinase activity after AAV2-MCT2 injection, suggest greater oxidative phosphorylation utilization in retina and optic nerve. The P1 amplitude of pattern electroretinogram was also significantly higher in ocular hypertensive mice with AAV2-MCT2 infection. Overall, expression of MCT2 via AAV2 infection improved retinal and optic nerve mitochondrial function and RGC survival in two models of glaucoma.
