According to a new study, decrease in the LEF1 gene is assumed to be liable for lithium resistance in people with bipolar disorder, thus leading to zero response to lithium. Bipolar disorder (BD) is a mental health condition defined by depressive and manic episodes that affect 2% of the world population.
In this study, the researchers examined patients with type I bipolar disorder who had engaged in genetic studies at Dalhousie University in Nova Scotia, Canada. All participants were Caucasian males in their 40s. The researchers extracted cells and performed RNA sequencing analysis. Results showed that Li-non-responsive (NR) neurons were distinct from control and Li-responsive (LR) neurons. Research also exhibited gene clustering of LR and NR samples clearly from controls, which implies that these gene sets embodied pathways that were obstructed in both LR and NR bipolar patient-derived neurons. The study also showed an “extensive dysregulation” of Wnt/β-catenin signaling in NR neurons.
Additionally, LEF1 was downregulated and Wnt/β-catenin signaling was impaired in NR neurons. “iPSC-derived neurons from NR and LR bipolar patients display notably different molecular changes that are linked with hyperexcitability, and that modulation of LEF1 may be essential in improving disease pathology in NR patients,” adds the study.
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Santos R, Linker SB, Stern S, et al. Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry. Published online January 4, 2021. doi:10.1038/s41380-020-00981-3