A genetic screen in a mouse model of Rett Syndrome, a severe neurological disorder with autism-like symptoms, identified a mutation in a gene involved in the synthesis of cholesterol. Treatment with a cholesterol-lowering statin drug lengthened the lifespan and improved some symptoms of the disorder in the mice, said a group of researchers led by those at Baylor College of Medicine in a report that appears online in the journal Nature Genetics.
"Treatments that affect cholesterol levels may have a role in treatment of patients with Rett Syndrome," said Dr. Monica Justice, professor of molecular and human genetics at BCM.
Defective protein MECP2
Rett Syndrome is a devastating order that affects mainly girls. The genetic mutation and resulting defective protein MECP2 begins to affect the youngsters when they are between 6 and 18 months. They begin to regress and their growth slows. They develop abnormal hand motions such as wringing. They lose the ability to move easily and they eventually lose the ability to speak or communicate. They exhibit some symptoms of autism. Mice without MECP2 show similar symptoms.
Justice said she and her colleagues did not anticipate the finding when they began to look for gene suppressors that could alleviate or correct the effects of the mutation in the gene MECP2 that causes Rett Syndrome.
The scan identified five suppressor genes, but one stood out because it was squalene epoxidase, the gene that codes for the enzyme that starts the committed cholesterol pathway.
"This stop codon mutation in squalene epoxidase down regulates the cholesterol pathway," said Justice. A stop codon stops the message in RNA from being translated into a protein.
In further studies in the mice, they found that the mutation in this gene perturbs the synthesis of cholesterol in the brain first and eventually disrupts the whole system.
"Statin drugs, however, work even better than the mutation," she said.
Statin drugs have a bad reputation in neurological diseases. Some people who take them notice memory loss and other problems. They have not proved beneficial in diseases such as Alzheimer’s.
Justice said her studies may show why that happens.
The brain is awash in cholesterol and is in constant need of it. If your body has too much cholesterol, it can store it as fat. However, when the brain has too much, it shuts down production within the brain.
Shutting down production stops the normal process by which cholesterol helps the brain achieve its goals and is then scavenged by glial cells and turned over normally.
"We think the mutation (in squalene epoxidase) and the statins are keeping the cholesterol pathway from peaking, sparking the shutdown," she said. "They keep it at a normal level."
They also found cholesterol problems outside the brain in mice that lacked MECP2.
Reduces cholesterol levels
"The brain has to turn over the old cholesterol to the body’s periphery (outside the brain)," she said. "When it does, it 'talks' to the liver and gut and tells them what is going on with cholesterol in the brain. We found that these mice were building up lipids (fats) in the liver." Normally, your body should store fat in adipose tissue, not in the liver.
Giving the statin actually improves the motor symptoms in the mice as well as reducing cholesterol levels in other parts of the body, she said.
The statins are not a cure. It does not affect breathing problems or a characteristic startle response to sound.
Others who took part in this research include Christie M. Buchovecky, Hannah M. Brown and Stephanie M. Kyle, all of BCM; Stephen D. Turley, Jeffrey G. McDonald, Benny Liu, Andrew A. Pieper and David W. Russell, all of the University of Texas Southwestern Medical School in Dallas; Wenhui Huang and Jay Shendure of the University of Washington in Seattle; and David M. Katz of Case Western University School of Medicine in Cleveland Ohio. Pieper is now with the University of Iowa Carver College of Medicine and Huang is with Fred Hutchinson Cancer Research Center in Seattle.