Intrinsic axonal degeneration pathways are critical for glaucomatous damage

Abstract

Glaucoma is a neurodegenerative disease affecting 70 million people worldwide. For some time, analysis of human glaucoma and animal models suggested that RGC axonal injury in the optic nerve head (where RGC axons exit the eye) is an important early event in glaucomatous neurodegeneration. During the last decade advances in molecular biology and genome manipulation have allowed this hypothesis to be tested more critically, at least in animal models. Data indicate that RGC axon degeneration precedes soma death. Preventing soma death using mouse models that are mutant for BAX, a proapoptotic gene, is not sufficient to prevent the degeneration of RGC axons. This indicates that different degeneration processes occur in different compartments of the RGC during glaucoma. Furthermore, the Wallerian degeneration slow allele (Wlds) slows or prevents RGC axon degeneration in rodent models of glaucoma. These experiments and many others, now strongly support the hypothesis that axon degeneration is a critical pathological event in glaucomatous neurodegeneration. However, the events that lead from a glaucomatous insult (e.g. elevated intraocular pressure) to axon damage in glaucoma are not well defined. For developing new therapies, it will be necessary to clearly define and order the molecular events that lead from glaucomatous insults to axon degeneration.

Severe, Early Axonal Degeneration Following Experimental Anterior Ischemic Optic Neuropathy

“…Annexin-V has previously been shown to label dying RGC cell bodies in many conditions, 6,25,30,[32][33][34][35][40][41][42] and our data demonstrated for the first time that annexin-V intensely labeled degenerating RGC axons after AION. Annexin-V staining was well visualized in vivo using cSLO and in vitro in retinal whole mount preparations 7 days after AION, and the staining pattern along degenerating axons was most prominent near the optic nerve head and occurred in a fragmented pattern, consistent with Wallerian-like degeneration.…”

Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma

“…We previously collected a large dataset of gene expression changes in the ONH across different stages of glaucoma (Howell et al , 2011a; Howell et al , 2011b; Howell et al , 2012a). Briefly, we previously performed gene expression analysis on eyes from female DBA/2J mice at 4, 8 and 10.5 months of age.…”

DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury

“…In glaucoma, an early critical site of insult to retinal ganglion cell (RGC) axons occurs in the region of the lamina as they exit the eye (Anderson and Hendrickson, 1974; Howell et al, 2007b; Quigley et al, 1983; Schlamp et al, 2006). Axonal injury initiates a cascade of signaling events both proximally and distally to the site of insult to trigger somal and axonal degeneration respectively (Abe and Cavalli, 2008; Coleman, 2005; Howell et al, 2012). The somal and axonal degeneration pathways in glaucoma appear to be molecularly distinct (Howell et al, 2012; Whitmore et al, 2005).…”

“…Axonal injury initiates a cascade of signaling events both proximally and distally to the site of insult to trigger somal and axonal degeneration respectively (Abe and Cavalli, 2008; Coleman, 2005; Howell et al, 2012). The somal and axonal degeneration pathways in glaucoma appear to be molecularly distinct (Howell et al, 2012; Whitmore et al, 2005). Bax deficiency prevents RGC death following axonal injury, but BAX is not required for axonal degeneration (Howell et al, 2007a; Howell et al, 2011; Li et al, 2000; Libby et al, 2005).…”