Lipid Buildup in Motor Neurons May Trigger ALS

This finding was published August 22, 2002, in the online edition of the Annals of Neurology.

Also called Lou Gehrig's disease, ALS is a progressive, fatal neurologic disease that occurs when specific nerve cells in the brain and spinal cord that control voluntary movement gradually deteriorate. The loss of these motor neurons causes the muscles under their control to weaken and wither away, leading to paralysis.

Comparison of spinal cord tissue extracted from people who had ALS to that from normal individuals revealed that levels of ceramides, cholesterol esters, and several other lipids were significantly elevated in the spinal cords of people with ALS.

A mouse model was developed with the mutated human gene copper/zinc-superoxide dismutase (Cu/Zn-SOD) incorporated into the genome. These mice, which displayed symptoms of ALS, were found to have increased levels of ceramides and cholesterol esters in their spinal cords.

Other experiments on motor neurons in tissue culture showed that exposure to free radicals caused an increase in the levels of ceramides and cholesterol esters in the cells. On the other hand, treatment of the neurons with a drug called ISP-1, which inhibits synthesis of sphingolipids, protected the cells from the effects of oxygen free radicals. The treated cells did not accumulate ceramides or cholesterol esters and did not 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,” explained Dr. Mark Mattson, lead author of the study and chief of the Laboratory of Neurosciences at the US National Institute on Aging (Baltimore, MD, USA; www.nih.gov). "This knowledge is now being used to develop drugs that potentially could prevent these abnormalities.”



Related Links:
National Institute on Aging