Lithium is considered the gold standard for the treatment of bipolar disorder (BD), but almost 70 percent of people with BD respond to it. This leaves them at risk for damage, which could be in life. Researchers at the Salk Institute have discovered that the culturist may be lying in gene activity – or lack thereof.
A new study led by Professor Salk and President Rusty Gage, published in the journal Molecular Psychiatry on January 4, 2021, shows that reducing gene activity called LEF1 disrupts function. normal neuronal and promotes hyperexcitability in brain cells – a sign of BD. The work could lead to a new drug target for BD as well as a biomarker for lithium nonresponsiveness.
“Only one-third of patients respond to lithium with the symptoms disappearing,” says Renata Santos, co-author of the study and research collaborator of Salk. “We were interested in the molecular mechanisms behind lithium resistance, which hindered lithium treatment in non-communicators. We found that LEF1 was deficient in neurons derived from nonspecifics. We were very pleased to see that it was possible to increase LEF1 and its dependent genes, making it a new target for therapeutic intervention in BD. “
The study builds on the earlier findings of the team, which reported that neurons of people with BD that do not respond to lithium are more likely to burn in a different way (they are easier stimulated, or hyperexcitable), and have an increase in potassium flow.
Topics in the team’s current study included lithium respirators, respondents and people without BD (controls). Using gas-cell methods, the researchers extracted neurons from the subjects ’blood cells and compared the genetic condition and behavior of the neurons for the three groups.
They looked at many genes across the board, but LEF1 stood out as one of the most different in terms of non-letters. In general, LEF1 plays a definite role in neuronal function by pairing with another protein called beta-catenin. The pairing usually activates other genes that regulate the level of activity in the neuron. In controlling or responding to neurons, lithium enables beta-catenin to pair with LEF1. But in non-liters, lithium is ineffective because LEF1 levels are too low for the pairs to occur, so there is no regulation of cell activity.
When the team administered valproic acid, a treatment that was frequently used for respondents, measurements showed higher levels of LEF1 and the activation of other relevant genes. And when the team silenced the LEF1 gene in control neurons, they found that the associated genes were not activated. Taken together, these results highlight the critical role of LEF1 in controlling neuronal hyperexcitability.
“When we silenced the LEF1 gene, the neurons became hyperexcitable,” says Shani Stern, co-author of the study and visiting scientist of Salk. “And when we used valproic acid, the sensitivity of LEF1 increased, and the hyperexcitability decreased. That indicates a causal relationship, which is why we believe that LEF1 may be a potential target for drug treatment. ”
LEF1 can also help researchers develop a screening test for responsiveness. Currently, clinicians are unable to determine whether a patient responds to lithium by administering a complete course of treatment, which could take a year.
Now, LEF1-controlled activity may be an indication that a patient is not responding to lithium, enabling a faster and more efficient approach to treatment.
Team members are already considering the next steps. These include looking at other cell types, such as astrocytes and GABAergic neurons, to fully understand the bipolar neural network; identifies other genes that may be beneficial to respondents; and the detection of other drugs that activate LEF1.
“LEF1 works in different ways in different parts of the body, so you can’t turn it on everywhere,” says Carol Marchetto, Salk’s co-author and research collaborator. “You want to be more precise, either activating LEF1 on a targeted basis or activating downstream genes relevant for lithium insensitivity.”
(This story was published from a wire group group without altering the text.)
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