New Light on the Downhill Path:
Where does cell death begin? A hopeful note.

Everyone agrees death of motor neurons is the Main Bad Thing in ALS. But for a disease under so much scientific scrutiny, we know surprisingly little about how it progresses in those critical nerve cells. That’s in part because researchers can’t anticipate motor neuron problems in people yet to develop symptoms. And even if they could, no noninvasive way exists to analyze nerve cells in live patients.

Says Glass, “We might save neurons before the point of no return.”

“We’ve nothing that ties weakness or death to loss of spinal motor neurons, though, of course, we assume that’s happening,” says Center neuroscientist Jonathan Glass at Emory University.

Recently, however, Glass clarified ALS’s march in motor neurons, using a model mouse with especially rapid disease. He also studied an early ALS patient who died unexpectedly after minor surgery.

The studies confirm suggestions that motor cell death begins well before mice or patients display symptoms. But the work also shows where it begins. Motor nerve cells first go downhill distally, Glass explains—at the part of the cell farthest from the nucleus. Then damage spreads backward toward the body of the cell. It’s a process called dying back.

“You see dying back in a number of degenerative diseases or toxic conditions in the nervous system,” says Glass. The neuropathy of some diabetes patients, for example, shows that pattern. The longest, largest nerve fibers—those that take a lot of energy to support—seem to be the most vulnerable, including motor neurons.

In the SOD1 mouse Glass used, symptoms rapidly appear at 80 to 90 days. The animals die at around 130 days. Glass sacrificed them at key points in the disease, counting and observing their nerve cell bodies, axons and muscle-neuron junctions.

The first signs of disease began at day 78, Glass says, when mice had trouble walking on a rotating rod. But their nerve cells had begun dying back before day 47—almost half of the connections to muscle had deteriorated by then. The patient Glass studied also showed damage far out in axons.

“No one has yet explained the dying back phenomenon,” Glass says. It could be some sub-lethal insult to nerve cells, he offers, that deprives distant parts of nutrition. Or perhaps nerve cells get “gummed up” with abnormal proteins that prevent transport of food and structural materials. Others fault transport in the other direction—toward the nucleus. Cells whose retrograde transport is blocked can die if that process can’t carry crucial nerve-sustaining growth factors back to the nucleus.

“Still, just knowing dying back occurs is important,” says Glass. “It means we might be able to intervene at the earliest symptom. We might save neurons before they reach the point of no return.”

Next > A Free Spirit Comes Home
Inspired by others who’ve helped raise money for research, Christy Sloan realized she, too, could make a difference.