title: 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.
authors.affiliation: ZMMK and Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Mi
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.forename: Robert
authors.initials: R
authors.lastname: Adalbert
authors.forename: Diana
authors.initials: D
authors.lastname: Wagner
authors.forename: Daniela
authors.initials: D
authors.lastname: Grumme
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
authors.forename: Stefan
authors.initials: S
authors.lastname: Arnhold
authors.forename: Klaus
authors.initials: K
authors.lastname: Addicks
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Richard R
authors.initials: RR
authors.lastname: Ribchester
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D008526:Medulla Oblongata / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009186:Myelin Sheath / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000473:pathology; D010641:Phenotype; D013116:Spinal Cord / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism; D014855:Wallerian Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D025801:Ubiquitin