Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress–induced death of motor neurons in amyotrophic lateral sclerosis
Version of Record online: 22 AUG 2002
Copyright © 2002 Wiley-Liss, Inc.
Annals of Neurology
Volume 52, Issue 4, pages 448–457, October 2002
How to Cite
Cutler, R. G., Pedersen, W. A., Camandola, S., Rothstein, J. D. and Mattson, M. P. (2002), Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress–induced death of motor neurons in amyotrophic lateral sclerosis. Ann Neurol., 52: 448–457. doi: 10.1002/ana.10312
- Issue online: 23 SEP 2002
- Version of Record online: 22 AUG 2002
- Manuscript Accepted: 17 MAY 2002
- Manuscript Revised: 16 MAY 2002
- Manuscript Received: 12 MAR 2002
Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons in the spinal cord resulting in progressive paralysis and death. The pathogenic mechanism of ALS is unknown but may involve increased oxidative stress, overactivation of glutamate receptors, and apoptosis. We report abnormalities in sphingolipid and cholesterol metabolism in the spinal cords of ALS patients and in a transgenic mouse model (Cu/ZnSOD mutant mice), which manifest increased levels of sphingomyelin, ceramides, and cholesterol esters; in the Cu/ZnSOD mutant mice, these abnormalities precede the clinical phenotype. In ALS patients and Cu/Zn-SOD mutant mice, increased oxidative stress occurs in association with the lipid alterations, and exposure of cultured motor neurons to oxidative stress increases the accumulation of sphingomyelin, ceramides, and cholesterol esters. Pharmacological inhibition of sphingolipid synthesis prevents accumulation of ceramides, sphingomyelin, and cholesterol esters and protects motor neurons against death induced by oxidative and excitotoxic insults. These findings suggest a pivotal role for altered sphingolipid metabolism in the pathogenesis of ALS.