ArticleProceedings of the National Academy of Sciences of the United States of America2017
Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 2 of them syntheses that pooled it.
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Who cites it
76 citing papers in PubMed, 2 syntheses or guidelines pooled it, 151 citations in OpenAlex.
- Cellular calcium in bipolar disorder: systematic review and meta-analysis.Molecular psychiatry · 2021Pooled it
- Mental health dished up-the use of iPSC models in neuropsychiatric research.Journal of neural transmission (Vienna, Austria : 1996) · 2020Pooled it
- The Mechanisms by Which RhoA Activity and Associated Synaptic Effects Are Controlled by the DISC1 Scaffolding-Like Protein.Biological psychiatry · 2026Article
- Unraveling the enigma: Post-translational modifications in psychiatric disorders and their regulatory mechanisms.Journal of translational internal medicine · 2026Article
- Prefrontal spine loss in neuropsychiatric disorders: circuit consequences for cognition.Frontiers in psychiatry · 2026Review
- Lithium-induced neuroprotection in bipolar disorder: Translational insights into cytoskeletal and proteomic mechanisms.IBRO neuroscience reports · 2025Review
- Bioinformatics Analysis of Persistent Dysregulated Expression of Genes Involved in HCV-Induced Neurological Disorders and Liver Injuries After DAA Treatment Through Weighted Gene Co-Expression Network Analysis.Health science reports · 2025Article
- Detecting suicide risk in bipolar disorder patients from lymphoblastoid cell lines genetic signatures.Translational psychiatry · 2025Article
- Neuronal Synaptic Communication and Mitochondrial Energetics in Human Health and Disease.Advances in experimental medicine and biology · 2025Review
- NEK4 modulates circadian fluctuations of emotional behaviors and synaptogenesis in male mice.Nature communications · 2024Article
- Increased regional activity of a pro-autophagy pathway in schizophrenia as a contributor to sex differences in the disease pathology.Cell reports. Medicine · 2024Article
- Effectiveness of ultra-long-term lithium treatment: relevant factors and case series.International journal of bipolar disorders · 2024Review
- Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.Translational psychiatry · 2024Article
- Exploring mood disorders and treatment options using human stem cells.Genetics and molecular biology · 2024Article
- Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.Molecular psychiatry · 2024Article
- Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated CaMolecular psychiatry · 2023Article
- Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.Research square · 2023Article
- Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder.European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology · 2023Article
- Role of microtubule actin crosslinking factor 1 (MACF1) in bipolar disorder pathophysiology and potential in lithium therapeutic mechanism.Translational psychiatry · 2023Review
- Lithium rescues dendritic abnormalities in Ank3 deficiency models through the synergic effects of GSK3β and cyclic AMP signaling pathways.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
51 authors at 15 institutions in 5 countries.
Funding
Abstract
The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.
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