Progressive loss of motor neuron function in wasted mice: effects of a spontaneous null mutation in the gene for the eEF1 A2 translation factor.
Wasted (wst) is a spontaneous autosomal recessive mutation in which the gene encoding translation factor eEF1A2 is deleted. Homozygous mice show tremors and disturbances of gait shortly after weaning, followed by motor neuron degeneration, paralysis, and death by about 28 days. We have now conducted a more detailed analysis of neuromuscular pathology in these animals. Reactive gliosis was observed at 19 days postnatal in wst/wst cervical spinal cord, showing a rostrocaudal gradient. This was followed a few days later by motor neuron vacuolation and neurofilament accumulation, again with a rostrocaudal progression. Thoracic/abdominal muscles from wst/wst mice aged 17 days showed evidence of progressive denervation of motor endplates, including weak synaptic transmission and retraction of motor nerve terminals. Similar abnormalities appeared in distal, lumbrical muscles from about 25 days of age. We conclude that spontaneous failure of eEF1A2 expression in the wasted mutant first triggers gliosis in spinal cord and retraction of motor nerve terminals in muscle, and then motor neuron pathology and death. The early initiation and rapid progression of motor unit degeneration in wst/wst mice suggest that they should be considered an important and accessible model of early-onset motor neuron degeneration in humans.
Newbery
Helen J
HJ
Medical Genetics, Molecular Medicine Center, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Gillingwater
Thomas H
TH
Dharmasaroja
Permphan
P
Peters
Josephine
J
Wharton
Stephen B
SB
Thomson
Derek
D
Ribchester
Richard R
RR
Abbott
Catherine M
CM
D000818:Animals; D004594:Electrophysiology; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D009154:Mutation; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D020648:Peptide Elongation Factor 1 / Q000235:genetics* / Q000378:metabolism*; D045442:Rotarod Performance Test; D019282:Wasting Syndrome / Q000235:genetics / Q000473:pathology
C503234:EEF1A2 protein, human; C503235:Eef1a2 protein, mouse; D020648:Peptide Elongation Factor 1