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Proc Natl Acad Sci U S A. 2017 May 30;114(22):E4462-E4471. doi: 10.1073/pnas.1700111114. Epub 2017 May 12.

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

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
2
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
3
Department of Psychiatry, Veterans Administration Medical Center, La Jolla, CA 92037.
4
Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92037.
5
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
6
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
7
Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
8
Mailman Research Center, McLean Hospital, Belmont, MA 02478.
9
Department of Psychiatry, Harvard Medical School, Boston, MA 02115.
10
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030.
11
Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA 15219.
12
Molecular Neurobiology Section, National Institute of Mental Health, Bethesda, MD 20892-1363.
13
Vala Sciences, Inc., San Diego, CA 92121.
14
Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0737.
15
Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
16
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada B3H 2E2.
17
Department of Neurology, Beth Israel-Deaconess Medical Center, Boston, MA 02215.
18
Department of Biology, Vrije Universiteit Brussels, 1050 Brussels, Belgium.
19
Department of Cinical Medicine, Örebro University, Örebro SE-701 82, Sweden.
20
Janssen Research & Development Labs, La Jolla, CA 92037.
21
Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02115.
22
Department of Neurosurgery, Harvard Medical School, Boston, MA 02115.
23
Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan.
24
Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, Wako 351-0198, Japan.
25
Department of Neurology, Beth Israel-Deaconess Medical Center, Boston, MA 02215; esnyder@sbp.edu goshima@med.yokahama-cu.ac.jp shaggarty@mgh.harvard.edu richard_sidman@hms.harvard.edu.
26
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, esnyder@sbp.edu goshima@med.yokahama-cu.ac.jp shaggarty@mgh.harvard.edu richard_sidman@hms.harvard.edu.
27
Department of Molecular Pharmacology & Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; esnyder@sbp.edu goshima@med.yokahama-cu.ac.jp shaggarty@mgh.harvard.edu richard_sidman@hms.harvard.edu.
28
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; esnyder@sbp.edu goshima@med.yokahama-cu.ac.jp shaggarty@mgh.harvard.edu richard_sidman@hms.harvard.edu.
29
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92037.

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

PMID:
28500272
PMCID:
PMC5465887
DOI:
10.1073/pnas.1700111114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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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