Abstract
Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype “wasted” (wst). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal. Although the mutation is said to be recessive, aged heterozygous mice have never been examined in detail; a number of other mouse models of motor neuron degeneration have recently been shown to have similar, albeit less severe, phenotypic abnormalities in the heterozygous state. We therefore examined the effects of ageing on a cohort of heterozygous +/wst mice and control mice, in order to establish whether a presumed 50% reduction in eEF1A2 expression was compatible with normal function. We evaluated the grip strength assay as a way of distinguishing between wasted and wild-type mice at 3–4 weeks, and then performed the same assay in older +/wst and wild-type mice. We also used rotarod performance and immunohistochemistry of spinal cord sections to evaluate the phenotype of aged heterozygous mice. Heterozygous mutant mice showed no deficit in neuromuscular function or signs of spinal cord pathology, in spite of the low levels of eEF1A2.
Highlights
The wasted mouse is a model for early onset severe motor neuron degeneration [1,2]
We subsequently found that the primary lesion was a 15.8 kb deletion which removed the first exon and promoter of the gene encoding a tissue-specific translation elongation factor called eEF1A2 [4]
In these studies both wild-type and heterozygous animals demonstrated improvement with practice in the rotarod test, which could be attributed either to learning or to beneficial effects of regular exercise. This is shown most clearly when only one month elapsed between tests; here, performance in all groups increased compared to performance in tests conducted every three months. This is consistent with results obtained on similar assays conducted on mice carrying the SOD1 G93A mutation [13], with both wild-type controls and transgenic mice showed evidence of learning
Summary
The wasted mouse is a model for early onset severe motor neuron degeneration [1,2]. The underlying mutation arose in 1972 at the Jackson lab, where it was shown to be recessive and autosomal [3]. The timing of the switch from eEF1A1 to eEF1A2 expression in postnatal neurons and muscle, which is complete by 21 days, fits perfectly with the timing of the onset of the phenotype in wasted mice; wst/wst homozygotes are outwardly normal until 21 days and deteriorate and die within the 7 days. During this time they lose muscle bulk, develop gait abnormalities and display changes in the spinal cord consistent with those seen in humans with motor neuron disease, including loss of motor neurons, perikaryal accumulation of neurofilaments and reactive gliosis [2]. Wasted mice perform increasingly poorly on the rotarod over the same period of time
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