Brain Advance Access originally published online on January 11, 2005
Brain 2005 128(2):405-416; doi:10.1093/brain/awh368
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Brain Vol. 128 No. 2 © Guarantors of Brain 2005; all rights reserved
The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice
1 ZMMK and Institute for Genetics and 2 Department of Anatomy I, University of Cologne, Cologne, Germany, 3 Division of Neuroscience, University of Edinburgh, Edinburgh, 4 The Babraham Institute, Babraham, Cambridge, UK, 5 Department of Degenerative Neurological Diseases, National Institute of Neuroscience, Kodaira, Tokyo and 6 Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan
Correspondence: Dr Michael Coleman, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK E-mail: michael.coleman{at}bbsrc.ac.uk
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.
* W. Mi and B. Beirowski contributed equally to this work
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