The WldS gene delays axonal but not somatic degeneration in a rat glaucoma model.
Glaucoma is a leading cause of blindness caused by progressive degeneration of retinal ganglion cells (RGCs) and their axons. The pathogenesis of glaucoma remains incompletely understood, but optic nerve (ON) axonal injury appears to be an important trigger of RGC axonal and cell body degeneration. Rat models are widely used in glaucoma research to explore pathogenic mechanisms and to test novel neuroprotective approaches. Here we investigated the mechanism of axon loss in glaucoma, studying axon degeneration in slow Wallerian degeneration (Wld(S)) rats after increasing intraocular pressure. Wld(S) delays degeneration of experimentally transected axons for several weeks, so it can provide genetic evidence for Wallerian-like degeneration in disease. As apoptosis is unaffected, Wld(S) also provides information on whether cell death results from axon degeneration or arises independently, an important question yet to be resolved in glaucoma. Having confirmed expression of Wld(S) protein, we found that Wld(S) delayed ON axonal degeneration in experimental rat glaucoma for at least 2 weeks, especially in proximal ON where wild-type axons are most severely affected. The duration of axonal protection is similar to that after ON transection and crush, suggesting that axonal degeneration in glaucoma follows a Wallerian-like mechanism. Axonal degeneration must be prevented for RGCs to remain functional, so pharmacologically mimicking and enhancing the protective mechanism of Wld(S) could offer an important route towards therapy. However, Wld(S) did not protect RGC bodies in glaucoma or after ON lesion, suggesting that combination treatments protecting both axons and cell bodies offer the best therapeutic prospects.
Beirowski
Bogdan
B
The Babraham Institute, Cambridge, UK.
Babetto
Elisabetta
E
Coleman
Michael P
MP
Martin
Keith R
KR
D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D002470:Cell Survival; D005901:Glaucoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D007834:Lasers; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020221:Optic Nerve Injuries; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D014855:Wallerian Degeneration / Q000235:genetics / Q000473:pathology
D009419:Nerve Tissue Proteins; C533642:Wld protein, rat