ReviewHow has DISC1 enabled drug discovery?
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.
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Cited by (32)
Effect of DISC1 polymorphisms on the long-term course of neurocognitive deficits in non-affective psychosis
2015, European PsychiatryCitation Excerpt :Thus, the effect of DISC1 sequence variability should be interpreted in the context of multiple gene-gene interactions, in which the final role of one gene/protein is dependent on its weight within a specific biological pathway. Furthermore, because the DISC1 protein is predominantly expressed in the hippocampus and cerebral cortex [62], it could be hypothesized that genetic variants can modify protein availability and, consequently, alter the efficiency of the pathways in which the protein is implicated in a more specific manner in these brain areas. As previously described, DISC1 peripheral expression is lower in patients with schizophrenia [50,43], and this lower DISC1 expression is correlated with reduced expression of some DISC1 partner proteins in these brain areas [35] as well as with cognitive performance and N-back-elicited activity in the pre-frontal cortex [50].
Risk genes for schizophrenia: Translational opportunities for drug discovery
2014, Pharmacology and TherapeuticsCitation Excerpt :DISC1 itself is unlikely to be a druggable target, although modulation of its post-translational modifications, vital to its many functions, may be a route to stabilise the protein (Hikida et al., 2012). Alternatively modulation of its signalling pathways by targeting interacting proteins such as AKT (see above), DPYSL2 (see below), GSK3β (see above), PDE4 (see below) or TNIK (see below) may represent potential therapeutic strategies (Wang et al., 2008; Soares et al., 2011). The DPYSL2 gene encodes a phosphoprotein with multiple roles during neurogenesis and in the maintenance of adult neuronal plasticity (Khanna et al., 2012).
Schizophrenia risk genes: Implications for future drug development and discovery
2011, Biochemical PharmacologyCitation Excerpt :Further imputes for elucidating the effect of variation in DISC1 comes from the recent association of a missense variant in DISC1 with ultra antipsychotic-resistant forms of schizophrenia [103]. While the evidence from these studies is preliminary, findings from DISC1 have encouraged the development of new ways to model core pathognomic features of schizophrenia in lab species [104]. It has been suggested that models based on highly penetrant genetic mutations such as DISC1 are among the highest in terms of construct validity of neuropsychiatric disorders [5].
Assessing the role of endooligopeptidase activity of Ndel1 (nuclear-distribution gene E homolog like-1) in neurite outgrowth
2010, Molecular and Cellular NeurosciencePreface promises kept: Robust discovery in psychiatric genetics
2010, Psychiatric Clinics of North America
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These Authors contributed equally to this manuscript.