Review How has DISC1 enabled drug discovery? Qi Wang, a,1 Hanna Jaaro-Peled, b,1 Akira Sawa, b,c,d and Nicholas J. Brandon a, ⁎ a Discovery Neuroscience, Wyeth Research, Princeton, NJ, USA b Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA c Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA d Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA Received 3 October 2007; revised 15 October 2007; accepted 16 October 2007 Available online 23 October 2007 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. © 2007 Elsevier Inc. All rights reserved. Keywords: DISC1; Psychiatric disorders; Schizophrenia; PDE4; Nudel/ Ndel1; Animal models Contents DISC1 as one of the strongest risk genes associated with major psychiatric illness ................. 187 DISC1 localization and the DISC1 interactome suggest a role at neuronal synapses ................ 188 DISC1 interactors as potential therapeutic targets for psychiatric disorders ................... 188 www.elsevier.com/locate/ymcne Mol. Cell. Neurosci. 37 (2008) 187 – 195 ⁎ Corresponding author. E-mail address: brandon@wyeth.com (N.J. Brandon). 1 These Authors contributed equally to this manuscript. Available online on ScienceDirect (www.sciencedirect.com). Ndel1–EOPA as a drug target ............... 188 DISC1 and PDE4: a challenging path to therapeutics . . . 189 Further psychiatric targets selected from the DISC1 interactome ........................ 190 DPYSL2, CamKKβ, and DISC1 ............. 190 DISC1 has promoted the development of animal models for mental diseases .................... 191 Concluding remarks .................... 192 Acknowledgments ..................... 192 References ......................... 192 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 adop- tion 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 association studies and emerging biology (Ishizuka et al., 2006; Porteous et al., 2006). DISC1 is the protein coding gene disrupted by the balanced (1;11) (q42.1;q14.3) translocation that cosegregates with schizophrenia, major depression, and bipolar disorder in a large Scottish family (Millar et al., 2000b; Millar et al., 2001). Since its discovery, DISC1 has been subjected to intensive genetic analysis, which have shown reproducible linkage between genomic regions of DISC1 and major mental diseases in Finnish, British, North American, and Chinese populations (Ekelund et al., 2001, 2004; Hennah et al., 2003; Hodgkinson et al., 2004, 2007; Macgregor et al., 2004; Callicott et al., 2005; Hamshere et al., 2005; Thomson et al., 2005b; Liu et al., 2006; Maeda et al., 2006; Zhang et al., 2006; Chen et al., 2007; Qu et al., 2007). Furthermore, a recent study has shown an association between DISC1 and Autism and Asperger 1044-7431/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.mcn.2007.10.006