Progressive Loss of Motor Neuron Function in Wasted Mice

Progressive Loss of Motor Neuron Function in Wasted Mice: Effects of a Spontaneous Null Mutation in the Gene for the eEF1A2 Translation Factor.
JNEN: Journal of Neuropathology & Experimental Neurology. 64(4):295-303, April 2005.
Newbery, Helen J PhD; Gillingwater, Thomas H PhD; Dharmasaroja, Permphan MD; Peters, Josephine PhD; Wharton, Stephen B MBBS, MRCPath; Thomson, Derek MIBiol; Ribchester, Richard R PhD, DSc; Abbott, Catherine M PhD

Abstract: 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.

Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity

Nogo, a protein inhibiting axonal regeneration, exhibits a characteristic isoform-specific pattern of expression in skeletal muscle of transgenic mice and patients with amyotrophic lateral sclerosis. Here, the increased levels of Nogo-A or Nogo-B in muscle biopsies of 15 amyotrophic lateral sclerosis patients significantly correlated with the severity of clinical disability and with the degree of muscle fiber atrophy. Nogo-A immunoreactivity was observed selectively in atrophic slow-twitch type I fibers. These results suggest that Nogo expression in muscle is a marker of amyotrophic lateral sclerosis severity.

From Ann Neurol 2005;57:553-556

Breakthrough In Stem Cell Research

In an Australian first, UNSW researchers have developed three clones of cells from existing human embryonic stem cells. The breakthrough could lead to new treatments for diabetes, Parkinson's disease and spinal cord injury.

"This cloning of cells involves a new technique, which is a very accurate way of extracting and then growing a single cell," said UNSW Senior Lecturer Dr Kuldip Sidhu, who is leading the research and is based at the Diabetes Transplant Unit (DTU) at the Prince of Wales Hospital, a major teaching hospital of UNSW. "There has only been one report of cloning of cells from human embryonic stem cells anywhere else in the world – in Israel."

By growing a human stem cell colony from a single cell, researchers are one step closer to deriving a homogenous population of cells of a particular type.

"There are about 230 different cell types in the body. All these cells are derived from three embryonic layers – one which forms the brain and spinal cord, another which forms the guts and liver and a third which forms muscles and bones," he said. "We need to establish a recipe to derive each of these from human embryonic stem cells, so they can be transplanted straight into the affected area of a patient.

"The insulin-producing cells, which are derived from the layer which also forms the gut and liver are the holy grail for diabetes researchers," said Dr Sidhu. "That's because they are destroyed in type-1 diabetes, which affects at least 100,000 people in Australia. So far there is no cure for it.

"Human embryonic stem cell research offers a permanent answer to the problem. It gives the hope that we can produce a pure population of those cells in large numbers and transplant them into the patient."
The researchers are currently in the discovery phase, where they are trying to characterise the three clonal lines they have developed.

"It is too early to say anything about these clonal lines, but one of them is inclined towards the cells which form the guts and liver," said Dr Sidhu.

Dr Sidhu and Professor Bernie Tuch, the Director of DTU have received a grant for US$140,000 for two years from the Juvenile Diabetes Research Foundation (JDRF) in the United States to continue their work.

EXERCISE SLOWS DEVELOPMENT OF ALZHEIMER'S-LIKE BRAIN CHANGES IN MICE

Physical activity appears to inhibit Alzheimer's-like brain changes in mice, slowing the development of a key feature of the disease, according to a new study. The research demonstrated that long-term physical activity enhanced the learning ability of mice and decreased the level of plaque-forming beta-amyloid protein fragments -- a hallmark characteristic of Alzheimer's disease (AD) -- in their brains.

Results of this study, conducted by Paul A. Adlard, Ph.D., Carl W. Cotman, Ph.D., and colleagues at the University of California, Irvine, are published in the April 27, 2005, issue of "The Journal of Neuroscience".

Compared to the sedentary animals, mice that had exercised for 5 months on the running wheels had significantly fewer plaques and fewer beta-amyloid fragments (peptides) in the cerebral cortex and hippocampus, approximately by 50 percent. Additional studies, of exercised animals at 10 weeks old, showed that the mechanism underlying this difference began within the first month of exercise.

"From other research, it is known that in the aging human brain, deposits of beta-amyloid normally increase. This
study tells us that development of those deposits can be reduced and possibly eliminated through exercise, at least in this mouse model."