Mixed signals to blame for restless legs syndrome

October 25, 2004

SAN DIEGO-Iron-deficient cells in the brain are mixing up central nervous system signals to the legs and arms causing the irresistible urges to move and creepy-crawly sensations that characterize restless legs syndrome (RLS), a Penn State College of Medicine study reports.

"Our previous studies established a physical cause for RLS showing certain cells in the brain were iron deficient," said James R. Connor, Ph.D., professor and vice chair for neurosurgery, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "We have now found a sequence of events that may connect that cellular iron deficiency to the uncontrollable movements of the disorder."

The study was presented today (Oct. 25, 2004) by Xinsheng Wang, M.D., Ph.D., postdoctoral fellow in Connor's laboratory, at the Society for Neuroscience's scientific meeting, Neuroscience 2004, held in San Diego. RLS, a syndrome that may affect 5 percent to 10 percent of the U.S. population, causes irresistible urges to move the legs and arms and is often accompanied by creepy-crawly sensations in the limbs. The sensations are only relieved by movement and become worse as the sun goes down, causing night after night of sleeplessness for those with RLS and their partners.

In normal individuals, cells in a portion of the middle brain called the substantia nigra control the production of tyrosine hydroxylase (TH), an enzyme. The cells also determine how much of the TH is phosphorylated, or activated. The active TH regulates the production of dopamine, a substance in the brain that transmits messages from the brain and central nervous system to the body, giving it instructions for normal functioning.

Connor's team found that people with RLS have very high levels of active TH. Although this should result in more dopamine being made, in fact, the proper regulation of dopamine production is only possible with both active TH and adequate levels of iron.

"We think the 'active form' has lost its feedback mechanism," Connor said. "The cell is getting a signal that more dopamine is needed so TH is made and shifted to the active form, but the activity is compromised because less iron is available. If the iron was present in sufficient amounts, the feedback process would signal the cells to stop or slow TH production."

Connor's team first made the connection between iron deficiency and elevated TH levels by examining the brains of iron deficient rats. After weaning, the rats were divided into two groups. One group was given a normal diet, and the second, an iron deficient diet. Half of those that were given the iron deficient diet were later put on a normal iron diet. At 65 days, all rats, regardless of diet, had elevated levels of TH drawing the connection between cellular iron deficiency in the brain and elevated TH. However, the TH levels of the rats that had started a normal diet immediately after weaning eventually returned to normal.

"This shows us that developmental iron deficiency can be reversed, but that extended iron deficiency cannot be," Connor said. In a second study using a human cell culture model, the research team exposed PC12 cells, which create dopamine, to a substance that removes iron from cells. As more of the substance was added to the cells and, consequently, more iron was removed, the expression of TH grew, connecting the cellular iron deficiency to elevated TH in human cells.

In a third study, brain tissues from eight individuals with RLS were compared to tissues from the brains of five healthy individuals. The brain tissue was acquired through the Restless Legs Syndrome Foundation's brain collection at the Harvard Brain Bank. As the animal and cell culture models suggested, the autopsy analysis of the brains of those with RLS showed that iron-deficient cells from the middle brain expressed high levels of TH compared to the non-RLS group.

"These results continue to support the idea that the brain dopaminergic system is altered in RLS and that the differences in the dopaminergic system are consistent with insufficient iron," Connor said.

These findings explain why some RLS sufferers find relief from taking dopaminergic drugs. Although not FDA-approved for the treatment of RLS, the drugs are used to calm tremors in those with Parkinson's disease. The dopaminergic agents replace dopamine in the brain and temporarily improve the nerve signal transmission to the body.

"Our next steps are to continue investigations of treatment strategies for RLS involving iron supplementation and dopamine agents to attempt to reach the normal balance between iron and dopamine in the brain," Connor said.

In addition to Connor and Wang, other study authors were: John Beard, Ph.D., and Byron Jones, Ph.D., Penn State University; and Christopher J. Earley, M.B., B.Ch., Ph.D., and Richard Allen, Ph.D., Johns Hopkins Bayview Medical Center.
-end-


Penn State

Related Dopamine Articles from Brightsurf:

Dopamine surge reveals how even for mice, 'there's no place like home'
''There's no place like home,'' has its roots deep in the brain.

New dopamine sensors could help unlock the mysteries of brain chemistry
In 2018, Tian Lab at UC Davis Health developed dLight1, a single fluorescent protein-based biosensor.

Highly sensitive dopamine detector uses 2D materials
A supersensitive dopamine detector can help in the early diagnosis of several disorders that result in too much or too little dopamine, according to a group led by Penn State and including Rensselaer Polytechnic Institute and universities in China and Japan.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Viewing dopamine receptors in their native habitat
A new study led by UT Southwestern researchers reveals the structure of the active form of one type of dopamine receptor, known as D2, embedded in a phospholipid membrane.

Significant differences exist among neurons expressing dopamine receptors
An international collaboration, which included the involvement of the research team from the Institut de Neurociències of the UAB (INC-UAB), has shown that neurons expressing dopamine D2 receptors have different molecular features and functions, depending on their anatomical localization within the striatum.

How dopamine drives brain activity
Using a specialized magnetic resonance imaging (MRI) sensor that can track dopamine levels, MIT neuroscientists have discovered how dopamine released deep within the brain influences distant brain regions.

Novelty speeds up learning thanks to dopamine activation
Brain scientists led by Sebastian Haesler (NERF, empowered by IMEC, KU Leuven and VIB) have identified a causal mechanism of how novel stimuli promote learning.

Evidence in mice that childhood asthma is influenced by the neurotransmitter dopamine
Neurons that produce the neurotransmitter dopamine communicate with T cells to enhance allergic inflammation in the lungs of young mice but not older mice, researchers report Nov.

Chronic adversity dampens dopamine production
People exposed to a lifetime of psychosocial adversity may have an impaired ability to produce the dopamine levels needed for coping with acutely stressful situations.

Read More: Dopamine News and Dopamine Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.