Review
How has DISC1 enabled drug discovery?

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Abstract

Growing genetic and clinical evidence has shown that disrupted-in-schizophrenia 1 (DISC1) is one of the most compelling risk genes for schizophrenia and other major mental disorders. The understanding of the role that DISC1 plays in neuronal development and cell signaling has been greatly enhanced by the identification of DISC1 binding partners, an appreciation of its expression during development and functional studies using RNA interference. But what is the impact of this explosion of data for psychiatric drug discovery? Though we are at a very early stage of our understanding of DISC1 biology, it is an important time to review what has already been achieved and to discuss its impact. DISC1 biology has enabled the identification of new therapeutic targets in the form of DISC1 binding partners and other molecules found within a large DISC1 interaction network, the so-called ‘DISC1 interactome’. We will review the better characterized of these interactions and also emphasize the richness of potential targets in the more poorly studied areas of the interactome. Furthermore, DISC1 has encouraged the development of new animal models for psychiatric disorders, which is critical for the study of disease biology. Thus, DISC1 may have the potential to not only point us in the direction of novel drug targets but also provide more relevant animal models for compound testing.

Section snippets

DISC1 as one of the strongest risk genes associated with major psychiatric illness

Schizophrenia, bipolar disorder, and major depression are severe debilitating psychiatric disorders. Family, twin, and adoption studies have shown that genetic factors play an important role in the development of these diseases and in the past decade a large number of putative risk genes have been identified, in particular for schizophrenia (Harrison and Weinberger, 2005). Among these, disrupted-in-schizophrenia 1 (DISC1) is one of the strongest candidate genes through genetic and clinical

DISC1 localization and the DISC1 interactome suggest a role at neuronal synapses

The DISC1 gene consists of 13 exons and extends over a genomic region of at least 300 kb. The Scottish translocation occurs between exons 8 and 9, from which a predicted C-terminal truncated protein is produced (Millar et al., 2001). Like many large proteins with multiple exons, splicing of DISC1 transcripts is complex. There are at least four splicing variants in humans, which are referred to as L (long), Lv (long variant), S (short), and Es (extremely short) (Taylor et al., 2003). Specific

DISC1 interactors as potential therapeutic targets for psychiatric disorders

At its discovery in 2000, DISC1 was a novel protein without any known homolog in human (Millar et al., 2001). Although it contained some well-characterized protein domains, such as coiled-coil domains, leucine-zipper domains, and nuclear localization and export signals, they did not reveal anything about protein function (Millar et al., 2000a, Millar et al., 2000b). To increase our understanding of this enigmatic protein, a large number of yeast two hybrid (Y2H) screens were performed by

Ndel1–EOPA as a drug target

A number of groups identified DISC1/Ndel1 interaction simultaneously and studied the function of the resultant complex from different perspectives (Ozeki et al., 2003, Brandon et al., 2004, Hayashi et al., 2005, Kamiya et al., 2005, Kamiya et al., 2006, Taya et al., 2007). The binding site of Ndel1 on DISC1 has now been refined to amino acids 788–849 (Fig. 1), which was lost in the putative truncated protein in the Scottish family (Ozeki et al., 2003, Brandon et al., 2004, Kamiya et al., 2006).

DISC1 and PDE4: a challenging path to therapeutics

One of the most exciting and novel partners identified from the DISC1 interactome was phosphodiesterase 4B (PDE4B), a member of a family of enzymes that hydrolyze the phosphodiester bond of the second messenger cyclic adenosine monophosphate (cAMP) (Camargo et al., 2007). In parallel, a balanced translocation in the PDE4B gene was found to be associated with schizophrenia (Millar et al., 2005). Furthermore, pharmacological and knockout mouse data had previously implicated PDE4 in depression and

Further psychiatric targets selected from the DISC1 interactome

PDE4B and Ndel1 may be considered the ‘low-hanging’ fruit of the DISC1 interactome as we search for the start points to initiate further studies into DISC1. They are either already a well-established drug target (PDE4B) or a relatively well-characterized DISC1 partner (Ndel1), so justifying the initial efforts to understand their relationship to DISC1. We have selected further DISC1 interacting molecules and developed a case for their consideration as a target. Additional experimental data are

DPYSL2, CamKKβ, and DISC1

DPYSL2 (dihydropyrimidinase-like 2) belongs to the DRP (dihydropyrimidinase-related protein) family, originally identified as homologs of human dihydropyrimidinase which catalyze the reversible hydrolytic ring opening of the amide bond in five- or six-membered cyclic diamides (Hamajima et al., 1996). DPYSL2 is highly expressed in the brain, especially during prenatal development, and is crucial for axonal outgrowth and guidance. It increases neurite elongation and branching, possibly through

DISC1 has promoted the development of animal models for mental diseases

There is a clear need for new animal models in psychiatric drug discovery. The need is two-fold: (i) to be able to test new compounds with some level of predictability of their effect in man (Fig. 2) and (ii) to understand disease biology better (Pangalos et al., 2007). As DISC1 has emerged as one of the leading schizophrenia risk genes, there is hope that DISC1-based animal models will provide better models of the disease.

It is still unclear what kinds of molecular changes occur as the result

Concluding remarks

The serendipity of the last 100 years of psychiatric drug development needs to change and the molecule DISC1 has the potential to be at the center of this revolution. DISC1 is enabling us to identify new targets and develop new animal models in which 1 day we will be able to test our new therapeutics designed against a DISC1 interactor or DISC1 regulated process. It is critical that DISC1 therapeutics can treat all patients and not just the few with DISC1 mutations. Fortunately, DISC1 seems to

Acknowledgments

Thanks to Menelas Pangalos and Karen Marquis for critically reading the manuscript.

References (83)

  • C.A. Hodgkinson et al.

    Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder

    Am. J. Hum. Genet.

    (2004)
  • K. Ishizuka et al.

    A review of disrupted-in-schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions

    Biol. Psychiatry

    (2006)
  • R. James et al.

    Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria

    Mol. Cell. Neurosci.

    (2004)
  • Y.L. Liu et al.

    A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: association with impairment of sustained attention

    Biol. Psychiatry

    (2006)
  • L. Ma et al.

    Cloning and characterization of DISC1, the mouse ortholog of DISC1 (disrupted-in-schizophrenia 1)

    Genomics

    (2002)
  • K. Maeda et al.

    Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder

    Biol. Psychiatry

    (2006)
  • J.K. Millar et al.

    Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia

    Genomics

    (2000)
  • K. Nakata et al.

    The human dihydropyrimidinase-related protein 2 gene on chromosome 8p21 is associated with paranoid-type schizophrenia

    Biol. Psychiatry

    (2003)
  • M.V. Pletnikov et al.

    PC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation

    Neurosci. Res.

    (2007)
  • D.J. Porteous et al.

    The genetics and biology of DISC1—an emerging role in psychosis and cognition

    Biol. Psychiatry

    (2006)
  • M.E. Shenton et al.

    A review of MRI findings in schizophrenia

    Schizophr. Res.

    (2001)
  • M.S. Taylor et al.

    Evolutionary constraints on the disrupted in schizophrenia locus

    Genomics

    (2003)
  • P.A. Thomson et al.

    Association between genotype at an exonic SNP in DISC1 and normal cognitive aging

    Neurosci. Lett.

    (2005)
  • C.P. Austin et al.

    DISC1 (disrupted in schizophrenia-1) is expressed in limbic regions of the primate brain

    NeuroReport

    (2003)
  • M. Boules et al.

    Neurotensin agonists: potential in the treatment of schizophrenia

    CNS Drugs

    (2007)
  • Brandon, N.J., Rotella, D.P., in press. Potential CNS applications for phosphodiesterase enzyme inhibitors. Annu. Rep....
  • D. Bromme et al.

    Thiol-dependent cathepsins: pathophysiological implications and recent advances in inhibitor design

    Curr. Pharm. Des.

    (2002)
  • K.E. Burdick et al.

    DISC1 and neurocognitive function in schizophrenia

    NeuroReport

    (2005)
  • K.E. Burgin et al.

    In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain

    J. Neurosci.

    (1990)
  • T. Byk et al.

    Identification and molecular characterization of Unc-33-like phosphoprotein (Ulip), a putative mammalian homolog of the axonal guidance-associated unc-33 gene product

    J. Neurosci.

    (1996)
  • J.H. Callicott et al.

    Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • L.M. Camargo et al.

    Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia

    Mol. Psychiatry

    (2007)
  • T.D. Cannon et al.

    Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory

    Arch. Gen. Psychiatry

    (2005)
  • S.J. Clapcote et al.

    Deletion polymorphism of DISC1 is common to all 129 mouse substrains: implications for gene-targeting studies of brain function

    Genetics

    (2006)
  • N. Craddock et al.

    Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology

    Schizophr. Bull.

    (2006)
  • S.G. Dastidar et al.

    Therapeutic benefit of PDE4 inhibitors in inflammatory diseases

    Curr. Opin. Investig. Drugs

    (2007)
  • J. Ekelund et al.

    Chromosome 1 loci in Finnish schizophrenia families

    Hum. Mol. Genet.

    (2001)
  • J. Ekelund et al.

    Replication of 1q42 linkage in Finnish schizophrenia pedigrees

    Mol. Psychiatry

    (2004)
  • T.K. Gandhi et al.

    Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets

    Nat. Genet.

    (2006)
  • Y. Goshima et al.

    Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33

    Nature

    (1995)
  • T.D. Gould et al.

    Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs

    Neuropsychopharmacology

    (2005)
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    These Authors contributed equally to this manuscript.

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