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PMID: 28500272 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 114 ·No. 22 ·2017-00-30 ·Pages E4462-E4471

Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao WN, Lalonde J, Nakamura H, Konopaske G, Sidor M, Pernia CD, Yamashita N, Wada M, Inoue Y, Nakamura F, Sheridan SD, Logan RW, Brandel M, Wu D, Hunsberger J, Dorsett L, Duerr C, Basa RCB, McCarthy MJ, Udeshi ND, Mertins P, Carr SA, Rouleau GA, Mastrangelo L, Li J, Gutierrez GJ, Brill LM, Venizelos N, Chen G, Nye JS, Manji H, Price JH, McClung CA, Akiskal HS, Alda M, Chuang DM, Coyle JT, Liu Y, Teng YD, Ohshima T, Mikoshiba K, Sidman RL, Halpain S, Haggarty SJ, Goshima Y, Snyder EY

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
CRMP2 dendrites posttranslational modification proteomics psychiatric disease modeling
MeSH Terms
Animals Bipolar Disorder/genetics,metabolism,physiopathology Brain Chemistry Calcium/metabolism Cells, Cultured Humans Induced Pluripotent Stem Cells/drug effects,physiology Intercellular Signaling Peptides and Proteins/chemistry,metabolism Lithium/pharmacology Mice Models, Biological Nerve Tissue Proteins/chemistry,metabolism Protein Processing, Post-Translational/drug effects Proteomics
Chemicals
Intercellular Signaling Peptides and Proteins Nerve Tissue Proteins collapsin response mediator protein-2 Lithium Calcium
Authors & Affiliations
51 authors, click to expand affiliations / ORCID
Tobe Brian T D
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037. | Department of Psychiatry, Veterans Administration Medical Center, La Jolla, CA 92037.
Crain Andrew M
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Winquist Alicia M
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Calabrese Barbara
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037. | Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037.
Makihara Hiroko
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Zhao Wen-Ning
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. | Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Lalonde Jasmin
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. | Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Nakamura Haruko
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Konopaske Glenn
Mailman Research Center, McLean Hospital, Belmont, MA 02478. | Department of Psychiatry, Harvard Medical School, Boston, MA 02115. | Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030.
Sidor Michelle
Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA 15219.
Pernia Cameron D
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Yamashita Naoya
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Wada Moyuka
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Inoue Yuuka
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Nakamura Fumio
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Sheridan Steven D
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. | Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Logan Ryan W
Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA 15219.
Brandel Michael
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Wu Dongmei
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
Hunsberger Joshua
Molecular Neurobiology Section, National Institute of Mental Health, Bethesda, MD 20892-1363.
Dorsett Laurel
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Duerr Cordulla
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Basa Ranor C B
Vala Sciences, Inc., San Diego, CA 92121.
McCarthy Michael J
Department of Psychiatry, Veterans Administration Medical Center, La Jolla, CA 92037. | Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0737.
Udeshi Namrata D
Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
Mertins Philipp
Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
Carr Steven A
Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
Rouleau Guy A
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada B3H 2E2.
Mastrangelo Lina
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
Li Jianxue
Department of Neurology, Beth Israel-Deaconess Medical Center, Boston, MA 02215.
Gutierrez Gustavo J
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Department of Biology, Vrije Universiteit Brussels, 1050 Brussels, Belgium.
Brill Laurence M
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
Venizelos Nikolaos
Department of Cinical Medicine, Örebro University, Örebro SE-701 82, Sweden.
Chen Guang
Janssen Research & Development Labs, La Jolla, CA 92037.
Nye Jeffrey S
Janssen Research & Development Labs, La Jolla, CA 92037.
Manji Husseini
Janssen Research & Development Labs, La Jolla, CA 92037.
Price Jeffrey H
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. | Vala Sciences, Inc., San Diego, CA 92121.
McClung Colleen A
Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA 15219.
Akiskal Hagop S
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0737.
Alda Martin ORCID
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada B3H 2E2.
Chuang De-Maw M
Molecular Neurobiology Section, National Institute of Mental Health, Bethesda, MD 20892-1363.
Coyle Joseph T
Mailman Research Center, McLean Hospital, Belmont, MA 02478. | Department of Psychiatry, Harvard Medical School, Boston, MA 02115.
Liu Yang
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
Teng Yang D
Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02115. | Department of Neurosurgery, Harvard Medical School, Boston, MA 02115.
Ohshima Toshio
Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan. | Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako 351-0198, Japan.
Mikoshiba Katsuhiko
Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan. | Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako 351-0198, Japan.
Sidman Richard L
Department of Neurology, Beth Israel-Deaconess Medical Center, Boston, MA 02215; [email protected] [email protected] [email protected] [email protected].
Halpain Shelley
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037. | Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037.
Haggarty Stephen J
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, [email protected] [email protected] [email protected] [email protected]. | Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
Goshima Yoshio
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; [email protected] [email protected] [email protected] [email protected].
Snyder Evan Y
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; [email protected] [email protected] [email protected] [email protected]. | Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037. | Department of Pediatrics, University of California, San Diego, La Jolla, CA 92037.
Conflict of Interest

Conflict of interest statement: R.C.B.B., L.M.B., G.C., J.S.N., H.M., and J.H.P. are employees of private companies. Their role in the study was solely as researchers with no financial or proprietary involvement.

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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1700111114
Email
[email protected]
[email protected]
[email protected]
[email protected]
Published
2017-00-30
Epub
2017-00-12
Pages
E4462-E4471
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC5465887
Subset
IM
Grants
NIDA NIH HHS · K01 DA038654 · United States
NIMH NIH HHS · RC2 MH090011 · United States
NIMH NIH HHS · R21 MH093958 · United States
NIMH NIH HHS · R33 MH087896 · United States
NIMH NIH HHS · R01 MH095088 · United States
NIMH NIH HHS · R01 MH087823 · United States
External Links
PubMed source DOI: 10.1073/pnas.1700111114 PMC Full Text View journal details
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