Dataset Information

Overexpression of Optic Atrophy Type 1 Protects Retinal Ganglion Cells and Upregulates Parkin Expression in Experimental Glaucoma.

ABSTRACT: Glaucoma is a neurodegenerative disease that features progressive loss of retinal ganglion cells (RGCs). Increasing evidences have revealed that impaired mitochondrial dynamics occurs early in neurodegenerative diseases. Optic Atrophy Type 1 (OPA1), a mitochondrial fusion protein, has recently been suggested to be a mitophagic factor. Our previous studies found that glaucomatous retinal damage may be ameliorated by an increase in mitochondrial OPA1. In this study, we explored the mechanism involved in OPA1 mediated neuroprotection and its relationship with parkin dependent mitophagy in experimental glaucoma models. Our data showed that overexpression of OPA1 by viral vectors protected against RGC loss, attenuated Bax expression, and improved mitochondrial health and mitochondrial surface area. Parkin expression and the number of mitophagosomes were upregulated in OPA1 overexpressed RGCs under glutamate excitotoxicity. While knockdown of OPA1 by siRNA decreased protein expression of parkin in RGCs under glutamate excitotoxicity. Two weeks after intraocular pressure (IOP) elevation, the LC3-II/I ratio and the LAMP1 expression were increased in OPA1 overexpressed optic nerve. These findings suggest that OPA1 overexpression may protect RGCs by ways of enhancing mitochondria fusion and parkin mediated mitophagy. Interventions to promote mitochondrial fusion and mitophagy may provide a useful strategy to battle against glaucomatous RGC loss.

SUBMITTER: Hu X

PROVIDER: S-EPMC6172338 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Overexpression of Optic Atrophy Type 1 Protects Retinal Ganglion Cells and Upregulates Parkin Expression in Experimental Glaucoma.

Hu Xinxin X Dai Yi Y Zhang Rong R Shang Kunte K Sun Xinghuai X

Frontiers in molecular neuroscience 20180928

Glaucoma is a neurodegenerative disease that features progressive loss of retinal ganglion cells (RGCs). Increasing evidences have revealed that impaired mitochondrial dynamics occurs early in neurodegenerative diseases. Optic Atrophy Type 1 (OPA1), a mitochondrial fusion protein, has recently been suggested to be a mitophagic factor. Our previous studies found that glaucomatous retinal damage may be ameliorated by an increase in mitochondrial OPA1. In this study, we explored the mechanism invol ...[more]

PMID: 30323741

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Project description:PurposeTo determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.MethodsWe produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by ?-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry.ResultsLosartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP.ConclusionsThe neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.

Dataset Information

Overexpression of Optic Atrophy Type 1 Protects Retinal Ganglion Cells and Upregulates Parkin Expression in Experimental Glaucoma.

Publications

Overexpression of Optic Atrophy Type 1 Protects Retinal Ganglion Cells and Upregulates Parkin Expression in Experimental Glaucoma.

Similar Datasets

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