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Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis
Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla CA, USA; Department of Psychiatry, Veterans Administration Medical Center, La Jolla CA, USA .
Örebro University, School of Health Sciences. Department of Cinical Medicine, Örebro University Hospital, Örebro, Sweden. (Experimentell neuropsykiatri)ORCID iD: 0000-0001-8102-1804
Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla CA, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA, USA.
Number of Authors: 51
2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, E4462-E4471 p., 1700111114Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Washington DC, USA: National Academy of Sciences , 2017. Vol. 114, no 22, E4462-E4471 p., 1700111114
Keyword [en]
posttranslational modification; proteomics; psychiatric disease modeling; CRMP2; dendrites
National Category
Psychiatry Neurosciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medicine; Molecular Medicine (Genetics and Pathology); Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-57888DOI: 10.1073/pnas.1700111114ISI: 000402296700020PubMedID: 28500272Scopus ID: 2-s2.0-85020051123OAI: oai:DiVA.org:oru-57888DiVA: diva2:1105386
Funder
NIH (National Institute of Health), R01MH087823
Note

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 

Available from: 2017-06-03 Created: 2017-06-03 Last updated: 2017-09-26Bibliographically approved

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