LEF1 gene a possible goal for drug improvement in bipolar dysfunction

Downregulation of the LEF1 gene may be responsible for lithium resistance in people with bipolar disorder who are unresponsive to lithium, according to a study published in Nature.

The researchers studied patients with Type I bipolar disorder who participated in genetic studies at Dalhousie University in Nova Scotia, Canada. All participants in the current study were white men in their forties. The researchers extracted cells and performed an RNA sequencing analysis.

The analysis showed that Li-non-responsive (NR) neurons differ from control and Li-responsive (LR) neurons. These differences increase with differentiation.

Research also revealed gene clustering from LR and NR samples that was markedly different from controls, suggesting that these gene sets represented “signaling pathways disrupted in both LR and NR bipolar patient-derived neurons” said the researchers. The researchers also found “extensive dysregulation of Wnt / β-catenin signaling in NR neurons”.

In addition, LEF1 was downregulated and Wnt / β-catenin signal transmission is impaired in NR neurons. The researchers concluded that “iPSC-derived neurons from bipolar NR and LR patients have markedly different molecular changes associated with hyperexcitability, and that modulation of LEF1 may be key to improving disease pathology in NR patients.” can. ”

Limitations of this study were the small sample size, which was composed entirely of men.

We also spoke to two of the study’s authors, Renata Santos, PhD, senior researcher at the Institute of Psychiatry and Neuroscience in Paris, and Carol Marchetto, PhD, senior researcher at the Salk Institute for Biological Studies.

1. What are the highlights of your study?

Lithium is a trademark in the treatment and research of bipolar disorder (BD). It has been used for 70 years and is still the best treatment for preventing manic episodes and the only one that prevents suicide, although only a third of patients respond with symptoms completely disappearing. Understanding how lithium works and why it doesn’t work helps to understand the disease and to find new drug targets. We were interested in what causes lithium resistance in neurons generated from induced pluripotent stem cells (iPSC) obtained from patients who are clinically unresponsive to lithium (NR). Our goal was to find targets for developing new therapies for BD, and we have found LEF1, which holds great promise as a new target for drug discovery.

2. Why is this study important now?

BD is a devastating disease that affects the daily life and social integration of patients and affects 2% of the world’s population. Lithium has been used for 70 years and second generation antipsychotics for 20 years as a first-line treatment to stabilize mood in up to 20-30% of unresponsive patients. Therefore, patients are often treated with complex polypharmacy, which leads to a high drug burden and high health care costs. Therefore, there is an urgent need to develop new treatments for BD that are more effective, more tolerable and safer (especially for children and pregnant women).

3. What did you find while looking for specific targets related to Li resistance? What surprised you about the results?

We found that LEF1, a terminal gene found in the Wnt signaling pathway, is suppressed in neurons generated from iPSCs in patients with bipolar disorder who are unresponsive to lithium treatment. The reduction in LEF1 was responsible for increased neuronal activity and lithium resistance in cultured neurons. We wanted to find new genes that are largely off the beaten track and are involved in bipolar disorder. We were surprised that so many genes in the Wnt signaling pathway were dysregulated in neurons from NR patients because this pathway is an important junction of cellular lithium action.

4. In your study you wrote: One hypothesis to explain hyperexcitability is the dysregulation of Wnt signal transmission. Why or how is Wnt signaling dysregulation important in terms of bipolar disorder?

In fact, lithium and other drugs used to treat patients alter the regulation of the Wnt signaling pathway. This is a basic cellular pathway; For example, it is involved in embryonic brain development and cancer.

5. What further research is required?

Research remains to be done to evaluate the potential of LEF1 as a target for drug discovery and to identify new potential therapies.


Santos R., Linker SB, Stern S. et al. Lack of LEF1 expression is linked to lithium resistance and overexcitability in neurons derived from patients with bipolar disorder. Mol psychiatry. Published online January 4, 2021. doi: 10.1038 / s41380-020-00981-3

This article originally appeared on Psychiatry Advisor

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