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Brain Advance Access published online on January 11, 2005
Brain, doi:10.1093/brain/awh368
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Brain © Guarantors of Brain 2005; all rights reserved
Received April 17, 2004
Revised August 12, 2004
Accepted November 1, 2004

Article

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

Weiqian Mi 1, Bogdan Beirowski 2, Thomas H. Gillingwater 3, Robert Adalbert 4, Diana Wagner 1, Daniela Grumme 1, Hitoshi Osaka 5, Laura Conforti 6, Stefan Arnhold 7, Klaus Addicks 7, Keiji Wada 8, Richard R. Ribchester 3, and Michael P. Coleman 4*

1 ZMMK and Institute for Genetics, University of Cologne, Cologne, Germany
2 ZMMK and Institute for Genetics, University of Cologne, Cologne, Germany; Department of Anatomy I, University of Cologne, Cologne, Germany
3 Division of Neuroscience, University of Edinburgh, Edinburgh, UK
4 ZMMK and Institute for Genetics, University of Cologne, Cologne, Germany; The Babraham Institute, Babraham, Cambridge, UK
5 Department of Degenerative Neurological Diseases, National Institute of Neuroscience, Kodaira, Tokyo, Japan; Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan
6 The Babraham Institute, Babraham, Cambridge, UK
7 Department of Anatomy I, University of Cologne, Cologne, Germany
8 Department of Degenerative Neurological Diseases, National Institute of Neuroscience, Kodaira, Tokyo, Japan

* To whom correspondence should be addressed.
Michael P. Coleman, E-mail: michael.coleman{at}bbsrc.ac.uk


  Abstract

Summary 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.
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