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Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis

Item Type:Article
Title:Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis
Creators Name:Tobe, B.T.D. and Crain, A.M. and Winquist, A.M. and Calabrese, B. and Makihara, H. and Zhao, W.N. and Lalonde, J. and Nakamura, H. and Konopaske, G. and Sidor, M. and Pernia, C.D. and Yamashita, N. and Wada, M. and Inoue, Y. and Nakamura, F. and Sheridan, S.D. and Logan, R.W. and Brandel, M. and Wu, D. and Hunsberger, J. and Dorsett, L. and Duerr, C. and Basa, R.C.B. and McCarthy, M.J. and Udeshi, N.D. and Mertins, P. and Carr, S.A. and Rouleau, G.A. and Mastrangelo, L. and Li, J. and Gutierrez, G.J. and Brill, L.M. and Venizelos, N. and Chen, G. and Nye, J.S. and Manji, H. and Price, J.H. and McClung, C.A. and Akiskal, H.S. and Alda, M. and Chuang, D.M.M. and Coyle, J.T. and Liu, Y. and Teng, Y.D. and Ohshima, T. and Mikoshiba, K. and Sidman, R.L. and Halpain, S. and Haggarty, S.J. and Goshima, Y. and Snyder, E.Y.
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.
Keywords:Posttranslational Modification, Proteomics, Psychiatric Disease Modeling, CSRP2, Dendrites, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:114
Number:22
Page Range:E4462-E4471
Date:30 May 2017
Official Publication:https://doi.org/10.1073/pnas.1700111114
PubMed:View item in PubMed

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