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Packard Scientist Sheds Light on the Earliest Flaws in ALS Mice One of the earliest signs that something is amiss in mouse models of ALS is a great slowing down, in their motor neurons, of what's called retrograde transport. That's the normal "backward" circulation of molecules from one end of a nerve cell — the part intimately near the muscle — through the cell’s long, fingerlike axon to the nucleus-containing nerve cell body. The process is an important one. Growth factors that muscle cells normally release, for example — agents needed both for nerve cell health and proper nerve-muscle "conversations" — travel via retrograde transport throughout nerve cells. For several years, researchers with the Packard Center and others have suspected ALS might disrupt transport, in part, because altering such a key process could cause death of neurons in a gradual way, as does the disease. And in ALS, where many changes occur at the cell level and where no specific cause has reared its head, studying transport is especially attractive because such problems do occur early on. A few weeks ago, a transport study appeared, using classic mutant SOD1 mouse models of ALS, that’s been attracting much attention in the field. Work by Packard Center scientist Elizabeth M.C. Fisher and colleague Linda Greensmith at the Institute of Neurology in London and their research team suggests that transport glitches occur far earlier and are far more important in the disease than anyone had suspected. "Indeed," Fisher says, "they may be a prime cause of neuronal death in neurodegenerative disorders such as ALS." Especially interesting is the fact that with the scientists’ approach, disease onset in the study’s model mice was dramatically delayed. Also, they lived, on average, 28 percent longer. For some time, Fisher has been exploring mice with mutations in the cell’s molecular motor that drives transport. In one such flaw, in a protein called dynein, mice show defects in retrograde axon transport and their motor neurons. There’s motor neuron death as well. The mice, dubbed legs at odd angles (Loa), are spotted by unusual body twisting. In the present experiment, reported in The Journal of Cell Biology,
the Greensmith/Fisher team crossed Loa mice with the SOD1 models of ALS.
“We were fully expecting the offspring to show major disability
and early death,” says Greensmith. But the results were a surprise.
Mice that carried both the mutant Loa and SOD1 genes did surprisingly
well, with delayed onset of disease and increased survival. More spinal
cord motor neurons survived; at 120 days old, the mice had muscles as
strong as normal animals — something that wouldn’t happen
in typical ALS mice. And of great interest to the team: speed of retrograde
transport in the double mutation mice was the same as that of healthy
mice. “What our work emphasizes,” Fisher says, “is how important normal axonal transport is to the health of neurons and that defects in it play a critical role in motor neuron degeneration in the model mice and likely in humans with the disease.” Rescuing cells from those defects, she says, can have “a clear beneficial effect on motor ability and life span.” At this month’s gathering of Packard Center investigators, all agreed that it was a definite puzzle that two different mutations known to harm motor neurons could significantly help animals when present together. It suggests that one flaw could in some way offset another, they said. But solving the puzzle could shed light on the basic cause of ALS, they say. |
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