1. Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis
- Author
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Fumio Nakamura, Husseini K. Manji, Namrata D. Udeshi, Hagop S. Akiskal, Jeffrey H. Price, Nikolaos Venizelos, Wen-Ning Zhao, Cordulla Duerr, Ryan W. Logan, Jeffrey S. Nye, Jasmin Lalonde, Steven D. Sheridan, Joseph T. Coyle, Toshio Ohshima, Yoshio Goshima, Michael McCarthy, Shelley Halpain, Barbara Calabrese, Joshua G. Hunsberger, Martin Alda, Yuuka Inoue, Gustavo J. Gutierrez, Stephen J. Haggarty, Brian T. D. Tobe, Cameron D. Pernia, Richard L. Sidman, Moyuka Wada, Hiroko Makihara, Laurence M. Brill, Glenn T. Konopaske, Yang Liu, De-Maw M. Chuang, Ranor C. B. Basa, Alicia M. Winquist, Yang D. Teng, Michelle M. Sidor, Steven A. Carr, Colleen A. McClung, Guy A. Rouleau, Katsuhiko Mikoshiba, Evan Y. Snyder, Laurel Dorsett, Lina Mastrangelo, Guang Chen, Jianxue Li, Haruko Nakamura, Andrew Crain, Philipp Mertins, Michael G. Brandel, Dongmei Wu, Naoya Yamashita, and Biology
- Subjects
0301 basic medicine ,Genetically modified mouse ,Proteomics ,Dendritic spine ,Bipolar Disorder ,Induced Pluripotent Stem Cells ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Nerve Tissue Proteins ,Biology ,Lithium ,Models, Biological ,Psykiatri ,03 medical and health sciences ,Mice ,0302 clinical medicine ,posttranslational modification ,proteomics ,psychiatric disease modeling ,CRMP2 ,dendrites ,Calcium flux ,mental disorders ,medicine ,Animals ,Humans ,Induced pluripotent stem cell ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Cells, Cultured ,Brain Chemistry ,Psychiatry ,Multidisciplinary ,Neurosciences ,030104 developmental biology ,medicine.anatomical_structure ,PNAS Plus ,Phosphorylation ,Intercellular Signaling Peptides and Proteins ,Calcium ,Neuron ,Collapsin response mediator protein family ,Neuroscience ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Intracellular ,Neurovetenskaper - 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 non-phosphorylated 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., Funding Agencies:NIH's Library of Integrated Network-based Cellular Signatures Program Viterbi Foundation Neuroscience Initiative Stanley Medical Research Institute R21MH093958 R33MH087896 R01MH095088 Tau Consortium California Institute of Regenerative Medicine training grants University of California, San Diego T32 training grant in psychiatry California Bipolar Foundation International Bipolar Foundation Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Ministry of Education, Science, Sports and Culture in Japan 42890001 RC2MH090011
- Published
- 2017