December 8, 2009
Rett Symptoms Stem From Gene Loss In Cells That Make Specific Neurotransmitters
Loss of the gene that causes Rett syndrome disrupts the production of neurotransmitters in specific nerve cells, causing the movement and behavioral problems typical of the disease, said a research team led by those at Baylor College of Medicine in a report online today in the Proceedings of the National Academy of Sciences.
"Abnormalities in MeCP2 (methyl-CpG binding protein) lead to decreased production of enzymes that control production of the neurotransmitters dopamine, norepinephrine and serotonin," said Dr. Jeffrey Neul, assistant professor of pediatrics "“ neurology at BCM and Texas Children's Hospital, and a senior author of the report. Neul is also assistant medical director of the Blue Bird Rett Center at BCM.
"This study, and in particular the data in the patients, confirmed our first ever clinical study on Rett syndrome," said Dr. Huda Zoghbi, professor of molecular and human genetics, pediatrics, neurology and neuroscience and a senior author of the report. In 1985, Zoghbi and her collaborators first found that the metabolites of dopamine and norepinephrine were decreased in the spinal fluid of six girls with Rett syndrome. (N Engl J Med. 1985 Oct 10;313(15):921-4. Metabolites are the breakdown products that remain after the neurotransmitters accomplish their tasks.)
While the finding made sense, it was hard to reproduce until standardized levels of such chemicals could be determined. Neurotransmitters carry messages from one cell to another in the form of chemical signals. Too little dopamine can result in movement problems such as those seen in Parkinson's disease. Low serotonin levels are associated with anxiety and aggressive behavior "“ behaviors also seen in Rett. Zoghbi, who is also a Howard Hughes Medical Institute investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's, discovered that mutations in the MECP2 gene cause Rett syndrome in 1999.
Rett syndrome is a neurodevelopmental disorder that affects mainly girls. As infants, girls with Rett syndrome seem normal for at least six months. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Many of their symptoms mirror those of autism. The disorder is estimated to affect 1 in 10,000 to 15,000 live female births.
In this study, the researchers analyzed the metabolites of the neurotransmitters in the spinal fluid of 64 girls and women with Rett syndrome and compared them to the levels in spinal fluid of more than 200 people who did not have the disorder. They found low levels of the metabolites for dopamine and serotonin.
They also found that levels of all three neurotransmitters were reduced in the brains of mice with a mutated Mecp2 gene, which causes a form of Rett syndrome in the animal. Further study showed that the neurons were producing too little of the neurotransmitters because MeCP2 binds to the promoters of the enzymes that are a critical step in the production of the neurotransmitters.
"We wanted to know what role MeCP2 plays in the neurons that produce the neurotransmitters," said Neul. Using a special process, they were able to "knock-out" the MeCP2 gene only in the subset of neurons that produced each neurotransmitter. He and Zoghbi credited first author and graduate student Rodney C. Samaco with pushing the work forward.
When they eliminated MeCP2 in the neurons that produce serotonin, only the serotonin levels decreased. When they eliminated it in the neurons that produce dopamine and norepinephrine, only the levels of those neurotransmitters decreased.
Symptoms paralleled neurotransmitter loss. When only dopamine and norepinephrine declined, the animal had movement problems. When only serotonin levels decreased, the animals had normal movement but were more aggressive.
"The pathophysiology (symptoms) of the disease is a cumulative effect of MeCP2 on different neuronal populations," said Neul. "Each contributes to the overall picture of the disease."
In the future, he said, he hopes to target the symptoms of the diseases by correcting the defect in the neurotransmitters.
"We could use this information to do some targeted therapeutics by modifying the dopamine, norepinephrine, and serotonin systems," Neul said.
An important negative finding is that loss of MeCP2 in the neurotransmitter-making cells did not cause breathing problems or death, said Neul.
"We have to start finding out what is causing the breathing abnormalities and deaths," Neul said. "It could be a cumulative effect that occurs when MeCP2 is lost from all of these neurotransmitters systems. We may need to consider therapy that modifies all of these systems to see a meaningful effect."
The findings may also have implications for other disorders that stem from neurotransmitter abnormalities "“ such as Parkinson's disease.
"Understanding the pathological mechanism that causes these abnormalities in Rett syndrome may give insight into the neurocircuitry that contributes to other kinds of diseases," Neul said.
Others who took part in the study include Caleigh Mandel-Brehma, Hsiao-Tuan Chaob, Christopher S. Ward, Sharyl L. Fyffe-Maricich, Christina Thaller, Steven M. Maricich and Daniel G. Glaze, all of BCM; Jun Ren and John J. Greer of the University of Alberta in Canada, Keith Hyland of Baylor University Medical Center in Dallas, Peter Humphreys of Children's Hospital of Eastern Ontario in Canada and Alan Percy of the University of Alabama at Birmingham. Sharyl L. Fyffe-Maricich and Stephen M. Maricich are now at Caste Western Reserve University School of Medicine in Ohio, and Hyland is with Medical Neurogenetics in Atlanta.
Funding for this work came from Autism Speaks, the National Institutes of Health, the International Rett Syndrome Foundation, the Simons Foundation and the Howard Hughes Medical Institute.
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