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Endogenous Cell Type–Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders

  • Brent Wilkinson
    Affiliations
    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Oleg V. Evgrafov
    Affiliations
    Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York
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  • DongQing Zheng
    Affiliations
    Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California
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  • Nicolas Hartel
    Affiliations
    Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California
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  • James A. Knowles
    Affiliations
    Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York
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  • Nicholas A. Graham
    Affiliations
    Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California
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  • Justin K. Ichida
    Affiliations
    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California

    Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

    Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Marcelo P. Coba
    Correspondence
    Address correspondence to Marcelo P. Coba, Ph.D., Keck School of Medicine, University of Southern California, Zilkha Neurogenetic Institute, 1501 San Pablo St, Los Angeles, CA 90033.
    Affiliations
    Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California

    Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
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      Abstract

      Background

      Disrupted in schizophrenia 1 (DISC1) has been implicated in a number of psychiatric diseases along with neurodevelopmental phenotypes such as the proliferation and differentiation of neural progenitor cells. While there has been significant effort directed toward understanding the function of DISC1 through the determination of its protein-protein interactions within an in vitro setting, endogenous interactions involving DISC1 within a cell type–specific setting relevant to neural development remain unclear.

      Methods

      Using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) genome engineering technology, we inserted an endogenous 3X-FLAG tag at the C-terminus of the canonical DISC1 gene in human induced pluripotent stem cells (iPSCs). We further differentiated these cells and used affinity purification to determine protein-protein interactions involving DISC1 in iPSC-derived neural progenitor cells and astrocytes.

      Results

      We were able to determine 151 novel cell type–specific proteins present in DISC1 endogenous interactomes. The DISC1 interactomes can be clustered into several subcomplexes that suggest novel DISC1 cell-specific functions. In addition, the DISC1 interactome in iPSC-derived neural progenitor cells associates in a connected network containing proteins found to harbor de novo mutations in patients affected by schizophrenia and contains a subset of novel interactions that are known to harbor syndromic mutations in neurodevelopmental disorders.

      Conclusions

      Endogenous DISC1 interactomes within iPSC-derived human neural progenitor cells and astrocytes are able to provide context to DISC1 function in a cell type–specific setting relevant to neural development and enables the integration of psychiatric disease risk factors within a set of defined molecular functions.

      Keywords

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      Linked Article

      • DISC1 and Its Protein Interactomes for Mental Function
        Biological PsychiatryVol. 85Issue 4
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          Advances in psychiatric genetics in the past decade have been amazing. The team effort at the global level has provided an invaluable encyclopedia. Furthermore, this information may be useful in identifying biomarkers and stratifying patients. Thus, its clinical utility may be high in the coming years. Nevertheless, it is unclear how much such rich information has contributed to a mechanistic understanding of disease pathophysiology. One concern is that the effect size of almost all genes identified by genome-wide association studies may be too small to generate model animals in an effective manner.
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