ReferenceID 6103
Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
Proc Natl Acad Sci U S A
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
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Record Fields
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- Reference Id
- 6103
- Evidence Id
- 22693
- Core Evidence Id
- 22693
- Source Reference Id
- 5475
- Herb2 Reference Id
- HBREF006272
- Subject Paper Key
- HBIN041411_33318177
- Pubmed Id
- 33318177
- Doi
- 10.1073/pnas.2014213117
- Paper Title
- Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
- Paper Abstract
- 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.
- Journal
- Proc Natl Acad Sci U S A
- Publish Year
- 2020
- Experiment Subject
- mouse; rat
- Experiment Type
- Animal Experiment
- Phenotype Related
- Neurodegeneration; Glaucoma; Irreversible Blindness; Optic Nerve Degeneration; Intraocular Pressure-sensitive Retinal Ganglion Cell Degeneration; Glaucomatous Neurodegeneration; Metabolic Disturbances
- Paper Title Cn
- Paper Title En
- Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
- Bilingual Status
- semi_complete