Lipid abnormalities linked to Lou Gehrig's disease

August 21, 2002

Abnormal accumulation of two common lipids in motor nerve cells could play a critical role in the development of amyotrophic lateral sclerosis (ALS), according to investigators at the National Institute on Aging (NIA) in Baltimore. The finding could help scientists develop drugs and other treatments that might one day slow or arrest the disease's progression.

"ALS is a terrible disease in which a fully functioning mind is trapped inside a body that is becoming progressively paralyzed. At the present time, nothing can be done for ALS, but we hope this newly established link between lipid regulation and the disease will hasten the development of new treatments," said Mark Mattson, Ph.D., lead author of the study* and chief of the NIA Laboratory of Neurosciences. Lipids are the building blocks of fats. The study is available online at the Annals of Neurology website, and will be published in the journal's September 2002 issue.

Also called Lou Gehrig's disease, ALS is a progressive, fatal neurological disease affecting as many as 20,000 Americans, with 5,000 new cases occurring in the United States each year. Patients usually die within five years of diagnosis. ALS occurs when specific nerve cells in the brain and spinal cord that control voluntary movement gradually degenerate. The loss of these motor neurons causes the muscles under their control to weaken and waste away, leading to paralysis. In some instances, the disease is inherited, but in most cases the cause is unknown.

But NIA scientists unearthed several new clues through a complex, multi-step investigation. After comparing spinal cord tissue extracted from people who had ALS with those who didn't, the investigators discovered that levels of ceramides, cholesterol esters and several other lipids were significantly elevated in the spinal cords of people with ALS.

To test whether these elevated levels of ceramides, a cell wall component, and cholesterol esters, a form of cholesterol, cause motor neuron degeneration associated with ALS, the investigators studied mice with a mutated human gene, called copper/zinc-superoxide dismutase (Cu/Zn-SOD), incorporated into their genome. The mice with this mutated gene, which causes some forms of inherited ALS in humans, developed progressive motor neuron degeneration in their spinal cords, became paralyzed and eventually died. As in humans, analysis of the spinal cords of these animals revealed increased levels of ceramides and cholesterol esters.

To determine what might cause these abnormalities in lipid metabolism, the investigators exposed mouse motor neurons to free radicals--molecules with unpaired electrons that can damage cells and tissues--because previous studies suggested that increased production of oxygen free radicals is involved in the onset and progression of ALS. As a result, ceramides and cholesterol esters are increased in the exposed cells, just as was found in motor neurons affected by ALS.

Building on this finding, Dr. Mattson and his colleagues conducted experiments to determine if accumulation of ceramides and cholesterol esters in these neurons could be blocked when treated with a drug called ISP-1. The drug prevents the formation of large membrane molecules called sphingolipids, which, in turn, produce ceramides. When exposed to oxygen free radicals, motor neurons treated with ISP-1 did not accumulate ceramides and cholesterol esters, nor did they degenerate. However, untreated motor neurons that were exposed directly to ceramides did deteriorate.

"Based on our study, ceramide accumulation appears to be both necessary and sufficient to explain the degeneration of spinal cord motor neurons in ALS," Dr. Mattson says. "This knowledge is now being used to develop drugs that potentially could prevent these abnormalities."

In addition to drugs, the NIA scientists are investigating whether changes in dietary intake of cholesterol and lipids involved in the formation of membrane sphingolipids might have an impact on an individual's susceptibility to ALS.
The NIA leads the Federal effort supporting and conducting biomedical, clinical, social, and behavioral research on aging. This effort includes research into the causes and treatment of Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders associated with age. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information Web site,

*Cutler RG, Pedersen WA, Camandola, S, Rothstein, JD, and Mattson, MP, "Evidence That Accumulation of Ceramides and Cholesterol Esters Mediates Oxidative Stress--Induced Death of Motor Neurons in Amyotrophic Lateral Sclerosis," Annals of Neurology¸ vol. 52 (2002).

NIH/National Institute on Aging

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