Differential protection of neuromuscular sensory and motor axons and their endings in Wld mutant mice

Abstract

Orthograde Wallerian degeneration normally brings about fragmentation of peripheral nerve axons and their sensory or motor endings within 24 -48 h in mice. However, neuronal expression of the chimaeric, Wld S gene mutation extends survival of functioning axons and their distal end-ings for up to 3 weeks after nerve section. Here we studied the pattern and rate of degeneration of sensory axons and their annulospiral endings in deep lumbrical muscles of Wld S mice, and compared these with motor axons and their terminals, using neurone-specific transgenic expression of the fluorescent proteins yellow fluorescent protein (YFP) or cyan fluorescent protein (CFP) as morphological reporters. Surprisingly, sensory endings were preserved for up to 20 days, at least twice as long as the most resilient motor nerve terminals. Protection of sensory endings and axons was also much less sensitive to Wld S gene-copy number or age than motor axons and their endings. Protection of y-motor axons and their terminals innervating the juxtaequatorial and polar regions of the spindles was less than sensory axons but greater than a-motor axons. The differences between sen-sory and motor axon protection persisted in electrically si-lent, organotypic nerve-explant cultures suggesting that re-sidual axonal activity does not contribute to the sensory-motor axon differences in vivo. Quantitative, Wld S -specific immunostaining of dorsal root ganglion (DRG) neurones and motor neurones in homozygous Wld S mice suggested that the nuclei of large DRG neurones contain about 2.4 times as much Wld S protein as motor neurones. By contrast, nuclear fluorescence of DRG neurones in homozygotes was only 1.5 times brighter than in heterozygotes stained under identical conditions. Thus, differences in axonal or synaptic protection within the same Wld mouse may most simply be explained by differences in expression level of Wld protein between neurones. Mimicry of Wld S -induced protection may also have applications in treatment of neurotoxicity or peripheral neu-ropathies in which the integrity of sensory endings may be especially implicated.Key words: Wallerian degeneration, axon, muscle spindle, sensory neurone, motor neurone, neuromuscular junction.There is growing evidence that degeneration of axon ter-minals precedes death of cell bodies in several forms of neurodegenerative disease (Selkoe, 2002;Gillingwater et al., 2003;Forero et al., 2006;Lin and Koleske, 2010). For example, in amyotrophic lateral sclerosis (ALS), some motor nerve terminals become sensitive to metabolic stress and degenerate before their cell bodies show overt path-ological signs, both in humans with ALS and in mouse models of the disease (Frey et al., 2000;Fischer et al., 2004;Schaefer et al., 2005;David et al., 2007). Under-standing the determinants and mechanisms of degenera-tion of axons and their terminals may therefore reveal molecular targets for mitigation of synaptopathies, ax-onopathies and other forms of neurodegenerative disease. An attractive, classic model of a...

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