It has been known since Waller’s description in 1850 that axons of damaged neurons degenerate on the distal side of the lesion. Wlds mice exhibit slow Wallerian degeneration, but while they are known to harbor an 85 kb tandem triplication, just how it protects them has remained uncertain. Advanced online publications in November 1 Annals of Neurology, and November 19 Nature Neuroscience, show that Wlds mice are protected by a chimeric gene arising from the triplication, which codes for a protein comprising the N-terminal end of ubiquitination conjugation factor E4B (Ube4b), and a nicotinamide mononucleotide adenylyltransferase (Nmnat), an enzyme involved in the synthesis of NAD+.
Michael Coleman of University of Cologne et al. showed that the chimeric transgene could protect mice from axonal degeneration in a dose-dependent manner. In the transgenic mice, the distal ends of the sciatic nerve axons were structurally preserved after the nerve was cut. In addition, synaptic vesicle recycling and synaptic transmission were maintained in these axons. Five days post-sectioning more than 7 percent of flexor digitorum brevis fibers responded to nerve stimulation, indicating that neuromuscular junctions were maintained. The transgenic mice had increased Nmnat activity but the steady-state levels of NAD+ were normal.
Meanwhile, Jonathan Glass et al. at Emory University, Atlanta, expressed the chimeric gene in cultured rat and mouse dorsal root ganglia (DRG) and then challenged the neurons with the neurotoxin vincristine. In contrast to wildtype cultured neurons, which died or whose axons stopped growing and shortened, cells expressing the chimera were resistant to axonal degeneration; after an initial growth arrest transgenic axons resumed growth at normal rates.
“These studies clearly have the potential to lead to therapeutics for ALS and other motor neuron diseases,” commented Jeff Rothstein, Johns Hopkins University. Other diseases of the CNS may also benefit from a deeper understanding of the processes involved in axon degeneration. “Most human neurologic diseases occur via processes which affect axons over a long period of time, which is akin to our neurotoxic model,” said Glass. “That axons can survive this type of insult and then regrow is fascinating.”
Reference:Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D, Thomson D, Gillingwater T, Court F, Conforti L, Fernando FS, Tarlton A, Andressen C, Addicks K, Magni G, Ribchester RR, Perry VH, Coleman MP.
Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nature Neurosci Advanced online publication 2001 November 19. Abstract
Wang MS, Fang G, Culver DG, Davis AA, Rich MM, Glass JD. The WldS protein protects against axonal degeneration: a model of gene therapy for peripheral neuropathy. Ann Neurol. 2001 Dec;50(6):773-9. Abstract
To view commentaries, primary articles and linked stories, go to the original posting on Alzforum.org here.
Copyright © 1996–2017 Biomedical Research Forum, LLC. All Rights Reserved.Share this: