From: ALS Center
http://www.alscenter.org/news/briefs/050719.cfm
alscenter@jhmi.edu
To: The ALS Community
Date: July 20, 2005
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.
A last finding, one prompted by the researchers' need for a closer look at the ALS models they was using, revealed that abnormal retrograde transport begins in utero, far earlier than anyone suspected.
"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.
About The Robert Packard Center for ALS Research at Johns Hopkins www.alscenter.org
Located in Baltimore, the Robert Packard Center for ALS Research at Johns Hopkins is a collaboration of scientists worldwide, working aggressively to develop new treatments and a cure for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The Center is the only institution of its kind dedicated solely to the disease. Its research is meant to translate from the laboratory bench to the clinic in record time.
Scientists and clinician members of the Packard Center are unsurpassed at moving drugs reliably and rapidly from preclinical experiments to human trials. They're linked, directly or indirectly, to the world's major pharmaceutical and biotechnology companies, which have both infrastructure and experience to make promising drugs into therapies.
Packard Center scientists are the first to propose and test a combination approach to drug therapy, a tactic that has worked for AIDS, cancer and other diseases.
ALS is a devastating, progressive neuromuscular disease that causes complete paralysis and loss of function - including the ability to eat, speak and breathe. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis.
For more information about The Robert Packard Center for ALS Research at Johns Hopkins, including information on its latest research and treatment, visit www.alscenter.org
Rebecca Berger The Robert Packard Center for ALS Research at Johns Hopkins 600 N. Wolfe Street, Meyer 6-109 Baltimore, MD 21287-5953 410.502.7677 phone 410.955.0672 fax rberger6@jhmi.edu www.alscenter.org