Targeting cholesterol
for ALS treatment

Published March 01 2017


In 2014, amyotrophic lateral sclerosis came into the limelight with the Ice Bucket Challenge. ALS, also known as Lou Gehrig’s disease, is a debilitating and fatal disorder that attacks the nerve cells. There is no cure for ALS. In a recent paper in the Journal of Lipid Research, researchers showed for the first time that patients with ALS have higher levels of cholesterol in the fluid surrounding the brain than people without the disease. The researchers propose that a potential therapeutic approach for ALS treatment could be to use drugs that reduce the levels of cholesterol in the brain.

ALS typically starts with twitching of muscles and ultimately leads to paralysis and respiratory failure. About 20,000 Americans have this disease at any given time. Riluzole, the only drug for ALS approved by the U.S. Food and Drug Administration, has been on the market since 1995 and shows only modest slowing of progression in a fraction of patients. There is no current treatment that stops or reverses ALS.

In the JLR study, led by William J. Griffiths of the Swansea University Medical School and Martin Turner of the University of Oxford in the U.K., the researchers investigated whether targeting cholesterol was an option for ALS treatment. Earlier studies indicated that an increase in cholesterol caused oxidative stress that led to neuronal death in ALS. Secondly, a gene critical for cholesterol metabolism called CYP27A1 was identified as a susceptibility gene that increased a person’s likelihood of contracting ALS. Some studies indicated that statins, drugs that reduce cholesterol, exacerbated ALS. However, a 2013 study definitively showed that the detrimental effects of statins were abolished when adjusted for age of onset and body mass index. “In the light of these studies, and considering that about 25 percent of the body’s cholesterol is present in brain, it seemed like cholesterol might be a potential target for ALS studies,” says Griffiths.

The investigators used serum, the clear liquid separated from clotted blood, from 35 ALS patients and 24 healthy individuals, and cerebrospinal fluid, the colorless fluid surrounding the brain and spinal cord, from 20 ALS patients and 15 healthy individuals for the study. They measured cholesterol and its metabolites by mass spectrometry.

Their analysis of the serum showed no significant differences in cholesterol or most of its metabolites between ALS patients and controls. However, Griffiths and colleagues observed the most interesting results in the cerebrospinal fluid. The level of cholesterol, specifically nonesterified cholesterol, was higher in the cerebrospinal fluid of the ALS patients.

Griffiths and his team explained this observation by pointing to the greater number of neurons that die during ALS. The dying neurons release more cholesterol from their membranes, and the metabolic pathways are unable to remove this excess cholesterol.

Alternatively, the investigators proposed, cholesterol metabolism through a pathway called LXRβ signaling could be defective in ALS patients. Support for this hypothesis comes from mice that are deficient in the LXRβ gene. These mice, similar to ALS patients, have neuronal inflammation and high cholesterol levels in the spinal cord. Furthermore, other metabolites of cholesterol that are part of the LXRβ signaling pathway also were reduced in the cerebrospinal fluid of ALS patients.

“We think that people with ALS are unable to dispose of the nonesterified cholesterol from brain efficiently, leading to the presentation of the disease,” explains Griffiths. Griffiths is optimistic that “not only will our work provide a method to diagnose ALS but be useful to stratify people for more efficient clinical trials and could also provide a route to development of a new drug to treat ALS.”

Monika Deshpande Monika Deshpande is a postdoctoral fellow at Johns Hopkins University.