From The Robert Packard Center for ALS Research at Johns Hopkins

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.