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B. Beirowski, M.P. Coleman, K.R. G. Martin; The Slow Wallerian Degeneration Gene (WLDS) Preserves Retinal Ganglion Cell Axons After Optic Nerve Transection and Crush in the Rat . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1263.
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Degeneration of retinal ganglion cell (RGC) axons is central to the pathogenesis of glaucoma and other optic neuropathies. Recent studies suggest that the axonal compartment of RGC undergoes programmed self–destruction independent of apoptosis. The WldS gene delays axonal degeneration in several mouse models of neurological disease and has been shown to postpone secondary cell body death in a model of motor neuron disease. Previously studied only in mice, the slow Wallerian degeneration phenotype was recently transferred to transgenic rats. We tested whether transgenic expression of WldS protected rat optic nerve axons from Wallerian degeneration following unilateral transection and crush injury. We also investigated the spatiotemporal nature of optic axonal degeneration.
Optic nerves of adult WldS and age matched wild–type rats were lesioned unilaterally 2–3 mm from the globe, transecting using a scalpel or crushing using watchmaker’s forceps. Transverse semi– and ultra–thin sections of the optic nerve at varying distances distally from the transection point were examined by light and electron microscopy. Immunocytochemistry for the WldS gene product was performed on retinal cryosections from WldS transgenic rats.
Expression of the WldS gene conferred a protective phenotype on optic nerves after transection or crush. Five days after transection almost all axons in the optic nerve 15 mm distal to the eye were protected at an ultrastructural level in WldS transgenic rats but most axons in wild–type controls were degenerated. The strength of neuroprotection was considerably weaker closer to the site of transection where we observed extensive axonal swellings with considerable accumulation of axoplasmic organelles and cytoskeletal components in WldS optic nerves. Immunocytochemistry revealed that the WldS protein was located in the RGC nuclei of transgenic rats.
We observed an unequivocal protective effect of the WldS gene on optic nerve axons following physical lesion paradigms. We suggest that WldS transgenic rats may provide a unique tool to assess the significance of axonal neuroprotection in rat glaucoma models. Our results provide a framework for testing the hypotheses that glaucomatous optic nerve degeneration follows a similar mechanism to Wallerian degeneration and that blocking this pathway could be important therapeutically.
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