A previously unknown brain mechanism that regulates anxiety has come to light. It allows a gene-altering protein to enter the nucleus of brain cells.
The protein goes by the name of methyl-CpG binding protein 2 (MeCP2), and scientists have linked it to anxiety behaviors.
The recent research could lead to new treatments for anxiety disorders that have fewer side effects, according to the team that carried it out at the Weizmann Institute of Science in Israel.
A paper on the study features in the journal Cell Reports.
“Current drugs for anxiety,” says senior study author Mike Fainzilber, who is a professor in the biomolecular sciences department at the Weizmann Institute, “are limited in their efficacy or have undesirable side effects, which also limit their usefulness.”
He suggests that the findings could help to overcome these drawbacks.
Most people experience anxiety now and again as part of everyday life. Anxiety disorders, however, are conditions in which the feelings of fear and uncertainty become overwhelming and do not go away. They typically last for 6 months or more.
The National Institutes of Health estimate that anxiety disorders affect around 1 in 5 people in the United States each year.
The study authors note that the gene MECP2 “is known to affect anxiety behaviors.”
Scientists have linked changes to MECP2 to a number of conditions. These include Rett syndrome and MeCP2 duplication syndrome, both of which feature anxiety among their symptoms.
All cells contain MeCP2, but the protein is “particularly abundant in brain cells.”
The protein regulates many genes that “play a role in normal brain function,” and particularly those that help to maintain synapses, or the connections between brain cells.
The researchers became particularly interested in how MeCP2 enters the nerve cell nucleus, which contains the cell’s genes.
They turned their attention to a family of transporter proteins called importins, which Prof. Fainzilber’s laboratory has been investigating for more than 20 years.
For most of that time, he and his team have focused on the role of importins in nerve cells of the peripheral nervous system.
However, after first study author Dr. Nicolas Panayotis joined the group in 2012, they shifted their attention to cells of the central nervous system, which includes the brain and spinal cord.
Using genetically engineered mice, they identified importin alpha-5 as the transporter protein that helps MeCP2 to enter the brain cell nucleus.
In a series of behavioral experiments, they then saw that mice lacking importin alpha-5 did not display anxiety under stress compared to normal littermates or those lacking other importins.
Further investigation revealed that without importin alpha-5, MeCP2 could not enter the nucleus of brain cells that control anxiety.
This had a knock-on effect on an enzyme that produces the signaling molecule S1P. It was the reduction in S1P signaling that brought down the anxiety.
In the final part of the study, the team searched for molecules that might target the mechanism.
They found that there are already some drugs in use that alter S1P signaling. One of these is fingolimod, which doctors prescribe for the treatment of multiple sclerosis.
When the researchers treated unmodified mice with fingolimod, the animals displayed fewer anxiety behaviors, at a level similar to that of the modified mice that lacked importin alpha-5.
The finding could explain why a clinical trial of fingolimod for the treatment of multiple sclerosis reported that the drug appeared to have a “calming effect on patients.”
Prof. Fainzilber says that they have now identified a number of candidate drugs that target the mechanism that they identified.
“Our findings have opened up a new direction for research into the mechanisms of anxiety.”
Dr. Nicolas Panayotis