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Abstract #90934 Published in IGR 21-4

Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin

Harder JM; Guymer C; Wood JPM; Daskalaki E; Chidlow G; Zhang C; Balasubramanian R; Cardozo BH; Foxworth NE; Deering KE; Ouellette TB; Montgomery C; Wheelock CE; Casson RJ; Williams PA; John SWM
Proceedings of the National Academy of Sciences of the United States of America 2020; 117: 33619-33627

See also comment(s) by Adriana DiPolo


Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.

The Jackson Laboratory, Bar Harbor, ME 04609.

Full article

Classification:

11.8 Neuroprotection (Part of: 11 Medical treatment)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)



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