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A. Dibas, T. Yorio; Abnormalities in Ubiquitin Proteasomal System: Role in Optic NerveE Damage in Glaucoma?. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4176.
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© ARVO (1962-2015); The Authors (2016-present)
The glaucomas represent a heterogeneous group of diseases that result in a progressive optic neuropathy characterized by functional and structural impairment of ocular tissues. The hallmark of glaucoma is the demyelination and degeneration of the optic nerve and death of retinal ganglion cells leading eventually to irreversible blindness. Axonal degeneration is likely to involve the ubiquitin-proteasome system (UPS). UPS activity is altered in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, as well as in aging. Ubiquitin hydrolase (UCH-L1 or PGP 9.5) activity and expression correlate with degeneration. Therefore, changes in the UPS activities were studied under insults inflicted on retinal ganglion cells induced by elevation of intraocular pressure and following intravitreal injection of endothelin-1 (ET-1).
Insults on retinal ganglion cells were induced by elevation of intraocular pressure in rat eyes or via intravitreal injection of endothelin. Real-time PCR was used for measuring changes in PGP9.5 and beta-actin. Also, changes in ubiquitinated proteins & PGP9.5 were followed in total retinal extracts using Western blotting. Inhibitors of the UPS were tested on affecting RGC-5 cells survival by measuring cyctochrome c release and DNA laddering. Also, the effect of hypoxia on UPS activity was evaluated by Western blotting in RGC-5 cells.
ET-1 injection resulted in increased ubiquitination of retinal proteins and decreased levels of PGP9.5 as judged by Western blotting. ET-1 injection and elevated IOP decreased mRNA levels of PGP9.5 as determined by RT-PCR. Lactacystin (1 µM), a potent inhibitor of the proteasomal complex, induced apoptosis in retinal ganglion cells (RGC-5) as judged by DNA laddering and the release of mitochondrial cytochrome C. Furthermore, exposure of RGC-5 to hypoxia was accompanied by increased ubiquitination, DNA laddering and the release of cytochrome C. More importantly, the concentration of PGP 9.5, a ubiquitin hydrolase, a key neuronal-specific enzyme, was decreased in hypoxic RGC-5.
Abnormalities in the UPS may lead to optic nerve axonal damage and provide new insight and aid in the development of new neuroprotective therapeutics targets for glaucoma.
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