A Greasy Way to Die
Authors: Davenport R. John 
Published: August 2003

Certain fatty molecules might grease the way toward death for motor neurons. According to a new study, mice and humans with amyotrophic lateral sclerosis (ALS) harbor excess lipids, which apparently activate cell death mechanisms in response to oxidative stress. The finding adds to researchers' understanding of how ALS kills neurons and might push ALS drug hunters to set their sights on lipid-producing enzymes.
The debilitating disease gradually destroys motor neurons in the spinal cord, ultimately killing patients by paralyzing their lungs. ALS is not a disease of advanced age, but it appears to share neuron-destroying mechanisms with age-related degenerative diseases such as Alzheimer's. An inherited form of ALS is caused by a mutation in the antioxidant enzyme superoxide dismutase (SOD), suggesting that oxidative stress contributes to the disease; inflammation or an overload of the excitatory neurotransmitter glutamate might also play a role. Previous work suggests that cells crank out lipids called ceramides when subjected to oxidative stress; these lipids act as signaling molecules that regulate cell suicide pathways. Perhaps lipids trigger the demise of neurons in ALS, proposed neuroscientist Mark Mattson of the National Institute on Aging Gerontology Research Center in Baltimore, Maryland, and colleagues.
The researchers obtained spinal cord samples from patients who had died of ALS and measured lipid concentrations. ALS samples contained more ceramides than did control tissue. Amounts of two related lipids, sphingomyelin and cholesterol esters, were also higher. To extend the finding, the team examined spinal cord samples from mice engineered to carry the SOD mutation responsible for some human familial ALS. Like their human counterparts, ALS mice had additional ceramide, sphingomyelin, and cholesterol esters. Mice that hadn't yet shown signs of the disease were also laden with lipids, suggesting that the fatty molecules contribute to the disease at its earliest stages.
The team next tested whether lipids mediate neurons' response to oxidative stress. The researchers bombarded cultured motor neurons from mice with a chemical that fires up the generation of superoxide molecules. The cells succumbed quickly. But in the presence of a molecule that blocks sphingolipid production, cells resisted the oxidative stress. Additional experiments revealed that blocking lipid synthesis also helped neurons survive an excess of glutamate, which pushes cells to churn out oxidizing free radicals. Together, the results suggest that motor neuron death in ALS requires a boost in lipid concentration. Diet might influence these lipid changes: A 2-year-old epidemiological study hints that a high-fat diet increases the risk of ALS. To further establish the link, says Mattson, scientists need to investigate whether ALS patients have higher blood concentrations of fatty acids.
"It's an absolutely first-rate study," says neurologist Stan Appel of Baylor College of Medicine in Houston. Researchers have focused on developing antioxidant and anti-inflammatory drugs for ALS, says Appel: "What this says is that we've been ignoring something that is downstream. A lot of us are going to look carefully at [the role of lipids]." Drugs that quell sphingolipid production might give motor neurons footing to survive ALS's oxidative stress.
--R. John Davenport

R. G. Cutler, W. A. Pedersen, S. Camandola, J. D. Rothstein, M. P. Mattson, Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis.
Ann. Neurol.
22 August 2002 [e-pub ahead of print].
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