The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice

Abstract

Axonal dystrophy is the hallmark of axon pathology in many neurodegenerative disorders of the CNS, including Alzheimer's disease, Parkinson's disease and stroke. Axons can also form larger swellings, or spheroids, as in multiple sclerosis and traumatic brain injury. Some spheroids are terminal endbulbs of axon stumps, but swellings may also occur on unbroken axons and their role in axon loss remains uncertain. Similarly, it is not known whether spheroids and axonal dystrophy in so many different CNS disorders arise by a common mechanism. These surprising gaps in current knowledge result largely from the lack of experimental methods to manipulate axon pathology. The slow Wallerian degeneration gene, Wld(S), delays Wallerian degeneration after injury, and also delays 'dying-back' in peripheral nervous system disorders, revealing a mechanistic link between two forms of axon degeneration traditionally considered distinct. We now report that Wld(S) also inhibits axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Both gracile nucleus (P < 0.001) and cervical gracile fascicle (P = 0.001) contained significantly fewer spheroids in gad/Wld(S) mice, and secondary signs of axon pathology such as myelin loss were also reduced. Motor nerve terminals at neuromuscular junctions continued to degenerate in gad/Wld(S) mice, consistent with previous observations that Wld(S) has a weaker effect on synapses than on axons, and probably contributing to the fact that Wld(S) did not alleviate gad symptoms. Wld(S) acts downstream of the initial pathogenic events to block gad pathology, suggesting that its effect on axonal swelling need not be specific to this disease. We conclude that axon degeneration mechanisms are more closely related than previously thought and that a link exists in gad between spheroid pathology and Wallerian degeneration that could hold for other disorders.

NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration

“…As reported previously, 9 heterozygous Wld S partially preserved NF-H 5 days after nerve lesion. However, transected nerves from transgenic lines 881 and 7104 were indistinguishable from wild-type nerves with no intact NF-H remaining ( Figure 5).…”

“…9 Thus, Nmnat1 expressed at levels similar to, or higher than Wld S protein, does not preserve axon continuity in vivo.…”

“…9,15,22 We therefore chose these lines for most of our subsequent investigations, but used also the other expressing lines, 891, 2460 and 7103, in some assays.…”

“…[1][2][3][4][5] Wallerian degeneration distal to an axonal injury is an important and relevant experimental model of axon degeneration in disease. A dominant mutation that delays Wallerian degeneration 10-fold in slow Wallerian degeneration (Wld S ) mice and rats, 6,7 also delays axon degeneration in genetic and toxic 'dying-back' disorders, 2,[8][9][10][11] indicating similarities in the underlying mechanisms. Thus, understanding the Wallerian degeneration mechanism should help to understand how axons degenerate in disease.…”

Mouse Forward Genetics in the Study of the Peripheral Nervous System and Human Peripheral Neuropathy

“…Therefore, the novel function exhibited by the Wld S protein appears to be intrinsic to the whole chimera [47]. While the molecular mechanism of Wld S protection remains enigmatic, crossing the Wld S mutant with other models of neuropathy, such as progressive motor neuronopathy [48], gracile axonal dystrophy [49], and the myelin protein zero (Mpz) knockout [50], has helped probe the role of axon degeneration in these disorders.…”