Death by Lipids?
MDA to Examine New Clues in ALS

by Margaret Wahl

A series of experiments reported in the Aug. 22 online edition of Annals of Neurology shows that excess accumulation of fatlike substances known as lipids occurs in spinal cord cells called motor neurons in amyotrophic lateral sclerosis, and that these substances appear to be directly involved in the progress of the disease.

Mark Mattson of the National Institute on Aging, led the study team, which included Jeffrey Rothstein, an MDA research grantee who also co-directs the MDA/ALS Center at Johns Hopkins University in Baltimore.

"This is a meaningful advance in that it opens up yet another new line of research, and one that could lead to better drug therapy," said Lewis P. Rowland, professor of neurology at Columbia University in New York and an MDA vice president. Only one drug, riluzole (brand name Rilutek), has U.S. Food and Drug Administration approval for treatment of ALS, and its effects are modest.

Sharon Hesterlee, MDA's Director of Research Development, said MDA is in touch with Mattson and is planning to look more closely at this work. "We'll look into it thoroughly," Hesterlee said, "just as we would any promising line of inquiry in this devastating disease."

The investigators on the new study say oxidative stress, a biochemical process that leads to the generation of toxic byproducts called free radicals, may cause overproduction of lipids in ALS-affected cells. (The basic cause of the oxidative stress isn't understood.) The lipids involved are ceramides and cholesterol esters. These in turn may directly cause cell death and almost certainly make cells more susceptible to oxidative stress, setting in motion a vicious cycle of motor neuron degeneration.

The researchers were able to break that cycle, at least in nerve cells in laboratory containers, using a substance called ISP-1. They say drugs could be developed that might have the same beneficial effect in patients, although details of drug development and delivery to cells in the nervous system would need considerable further study.

Such drugs might not get at the "root cause" of most cases of ALS, says Rowland, former director of the MDA/ALS Center at Columbia-Presbyterian Medical Center, but that might not matter.

"If you have a cascade of events and you can block the ultimate one that's causing the damage, that's all right," he said. He noted that the apparent therapeutic effect of ISP-1 suggests that the changes in lipid levels are actually a cause, and not just a result, of cell death in ALS.

When asked about the role of diet and cholesterol control in preventing or slowing the course of ALS, Rowland was skeptical, at least based on current evidence. "I don't think high blood cholesterol is a known risk factor for ALS," he said. Noting that there's little or no evidence that dietary cholesterol increases ALS risk, Rowland said, "I would count more on drug therapy than diet in this disease."

MDA spends some $5 million for ALS research annually and conducts a comprehensive ALS clinical program, including the operation of 28 MDA/ALS research and clinical centers across the country.