Journal Article

The slow Wallerian degeneration gene, <i>Wld</i><sup>S</sup>, inhibits axonal spheroid pathology in gracile axonal dystrophy mice

Weiqian Mi, Bogdan Beirowski, Thomas H. Gillingwater, Robert Adalbert, Diana Wagner, Daniela Grumme, Hitoshi Osaka, Laura Conforti, Stefan Arnhold, Klaus Addicks, Keiji Wada, Richard R. Ribchester and Michael P. Coleman

in Brain

Published on behalf of The Guarantors of Brain

Volume 128, issue 2, pages 405-416
Published in print February 2005 | ISSN: 0006-8950
Published online January 2005 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awh368
The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice

Show Summary Details

Preview

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, WldS, 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 WldS 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/WldS 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/WldS mice, consistent with previous observations that WldS has a weaker effect on synapses than on axons, and probably contributing to the fact that WldS did not alleviate gad symptoms. WldS 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.

Keywords: axon; axonal spheroid; gracile axonal dystrophy; ubiquitin; Wallerian degeneration; APP = amyloid precursor protein; gad = gracile axonal dystrophy; GFAP = glial fibrillary acidic protein; H & E = haematoxylin and eosin; NMJ = neuromuscular junction; PFA = paraformaldehyde; PNS = peripheral nervous system; WldS = slow Wallerian degeneration gene, mutation or mice; WldS = slow Wallerian degeneration protein; YFP = yellow fluorescent protein

Journal Article.  8436 words.  Illustrated.

Subjects: Neurology ; Neuroscience

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.