LEF1 gene a possible target for drug development for bipolar disorder
Downward regulation of LEF1 gene may be responsible for lithium resistance in people with bipolar disorder who do not respond to lithium according to a study published in Nature.
Researchers studied patients with bipolar I disorder who participated in genetic studies at Dalhousie University in Nova Scotia, Canada. All of the participants in the current study were white males in their 40s. The researchers extracted cells and performed an RNA sequencing analysis.
Analysis showed that Li-non-reactive (NR) neurons are distinct from control and Li-reactive (LR) neurons. These differences increase throughout the differentiation.
The research also showed the clustering of genes from the LR and NR samples distinctly from the controls, suggesting that these sets of genes “represented pathways that were disrupted in bipolar neurons derived from LR and NR patients,” the researchers said. . The researchers also discovered a “significant disruption of Wnt / β-catenin signaling in NR neurons”.
Furthermore, LEF1 was downregulated and Wnt / β-catenin signaling is altered in NR neurons. The researchers concluded that “iPSC-derived neurons from NR and LR bipolar patients exhibit very different molecular changes that are associated with hyperexcitability and this modulation of LEF1 may be the key to improving disease pathology in NR patients.
The limitations of this study were the small sample size, which consisted only of men.
We also spoke with two of the study’s authors, Renata Santos, PhD, senior researcher at the Paris Institute of Psychiatry and Neuroscience, and Carol Marchetto, PhD, senior researcher at the Salk Institute for Biological Studies.
1. What are the highlights of your study?
Lithium is a hallmark in the treatment and research of bipolar disorder (TB). It has been used for 70 years and it is still the best treatment to prevent manic episodes and the only one that prevents suicide, although only a third of patients will respond with complete disappearance of symptoms. Understanding how lithium works and also why it does not contribute to our knowledge of the disease and to the search for new drug targets. We investigated the causes of lithium resistance in neurons generated from induced pluripotent stem cells (iPSCs) derived from patients who do not clinically respond to lithium (NR). Our goal was to find targets for the development of new treatments for BM and we found LEF1 which shows promise as a new target for drug discovery.
2. Why is this study important now?
TB is a devastating disorder that impacts the daily life and social integration of patients, affecting 2% of the world’s population. Lithium has been used for 70 years and second-generation antipsychotics for 20 years as first-line treatments for mood stabilization with up to 20-30% of patients unresponsive. Therefore, patients are frequently treated with complex polypharmacy, resulting in high drug load and high health care costs. Therefore, there is an urgent need to develop new treatments for TB that are more effective, tolerable and safe (especially for children and pregnant women).
3. What did you find when you searched for specific targets related to Li resistance? What surprised you about the results?
We found that LEF1, a terminal gene of the Wnt signaling pathway, is repressed in neurons generated by iPSCs in patients with bipolar disorder who do not respond to lithium therapy. Reduction of LEF1 was responsible for the increase in neuronal activity and lithium resistance in cultured neurons. We wanted to find new genes, mostly outside of the known pathways, involved in bipolar disorder. We were surprised to find so many poorly regulated genes in the Wnt signaling pathway in neurons derived from NR patients, as this pathway is a major hub of cellular lithium action.
4. In your study, you wrote: One hypothesis to explain hyperexcitability is the dysregulation of Wnt signaling. Why or how is disruption of Wnt signaling important in bipolar disorder?
In fact, lithium and other drugs used to treat patients alter the regulation of the Wnt pathway. It is a fundamental cell signaling pathway; it’s involved in embryonic brain development and cancer, for example.
5. What additional research is needed?
Research is still needed to assess the potential for LEF1 as a target for drug discovery and for finding potential new treatments.
Santos R, Linker SB, Stern S, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from patients with bipolar disorder. Mol Psychiatry. Published online January 4, 2021. doi: 10.1038 / s41380-020-00981-3