Decreased LEF1 Gene Activation Could Explain Lithium Resistance

Decreased LEF1 Gene Activation Could Explain Lithium Resistance

Patients with bipolar disorder (BD) experience manic and depressive mood swings, which can be life threatening. While the symptoms can be managed with lithium, only a third of BD patients respond to lithium treatment. The reasons why so many patients have lithium resistance is unclear, but new research indicates this could be linked to the activity, or lack of it, of a gene called LEF1.

Around 2% of the world’s population suffer from BD and two thirds do not respond to lithium treatment. A study, led by Salk Professor and President Rusty Gage, sought to identify the molecular mechanisms involved in lithium resistance.

The researchers harvested blood cells from BD patients who responded to lithium, nonresponders, and individuals without BD, created induced pluripotent stem cells, and used them to grow hippocampal dentate gyrus-like neurons. The researchers analyzed the genetic differences and gene activity in all three groups and identified the LEF1 gene as being a potential cause of resistance.

The LEF1 gene is important for regulating neuronal activity. The LEF1 protein encoded by the gene binds with a second protein, beta-catenin, and the pairing regulates neuronal function by activating other genes. In both the non-BD (control) group and patients who responded to lithium treatment, the LEF1 gene allows the pairing to occur; however, in nonresponders, the level of LEF1 is too low for the pairing to occur so cell activity is not regulated.

BD patients who do not respond to lithium treatment are often prescribed valproic acid. The researchers found that LEF1 levels and relevant gene activity increased in nonresponders’ neurons when valproic acid was administered. The researchers also silenced the LEF1 gene in control group neurons and found other relevant genes were not activated and neurons became hyperexcitable. The findings suggest that the LEF1 gene plays an important role in controlling neuronal hyperexcitability and could serve as a target for drug therapy.

However, targeting the LEF1 gene with drugs is not straightforward, as while the gene plays an important role in regulating neuronal activity the gene works in different ways in other parts of the body, so it is not as easy as turning the gene on everywhere. Activation would need to be more specific or target downstream genes that are relevant for lithium nonresponders.

The researchers are planning further studies to gain a better understanding of the neural network of BD patients as a whole and will search for other genes that could be beneficial for nonresponders which could potentially be targeted, in addition to searching for drugs that could be used to selectively activate the LEF1 gene.

A LEF1 targeted therapy is likely to take many years, but in the meantime the research could help many BD patients. It can take up to a year after starting lithium treatment to determine whether it has been effective. If a test is developed that assesses LEF1 gene activity, it could be used to determine whether a BD patient would be likely to respond to lithium treatment, and result in faster and more effective therapy.

You can read more about the study in the paper – Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients – which was recently published in the journal Molecular Psychiatry. DOI: 10.1038/s41380-020-00981-3

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