DISC1-binding proteins in neural development, signalling and schizophrenia

Abstract

In the decade since Disrupted in Schizophrenia 1 (DISC1) was first identified it has become one of the most convincing risk genes for major mental illness. As a multi-functional scaffold protein, DISC1 has multiple identified protein interaction partners that highlight pathologically relevant molecular pathways with potential for pharmaceutical intervention. Amongst these are proteins involved in neuronal migration (e.g. APP, Dixdc1, LIS1, NDE1, NDEL1), neural progenitor proliferation (GSK3β), neurosignalling (Girdin, GSK3β, PDE4) and synaptic function (Kal7, TNIK). Furthermore, emerging evidence of genetic association (NDEL1, PCM1, PDE4B) and copy number variation (NDE1) implicate several DISC1-binding partners as risk factors for schizophrenia in their own right. Thus, a picture begins to emerge of DISC1 as a key hub for multiple critical developmental pathways within the brain, disruption of which can lead to a variety of psychiatric illness phenotypes.

Fig. 1

22 known DISC1-interacting proteins, the majority of which are found in or around the centrosome. Proteins which are known to bind directly to each other are linked by thick black lines, while proteins which are known to co-exist in the same complex, but for which a direct-interaction has, to our knowledge, yet to be demonstrated are linked by grey dashed lines. The circle linking dynein, dynactin, LIS1, NDE1 and NDEL1 signifies that these five proteins complex with each other. Note that the DISC1-CEP290, DISC1-AKAP450 and TNIK-AKAP450 interactions have only been shown by yeast-2-hybrid screening and remain to be confirmed, while Grb2 binds only to a single isoform of PDE4D. Data on interactions with DISC1 and between DISC1-binding partners were taken from the following papers: (Beard et al., 1999; Bradshaw et al., 2008, 2009; Brandon et al., 2004; Burdick et al., 2008; Camargo et al., 2007; Chang et al., 2006; Collins et al., 2008; Ewing et al., 2007; Faulkner et al., 2000; Feng et al., 2000; Guo et al., 2006; Hattori et al., 2007; Hirohashi et al., 2006; Hutchins et al., 2010; Kim et al., 2004, 2008b; Kitagawa et al., 2000; McCahill et al., 2005; Millar et al., 2003, 2005; Miyoshi et al., 2004; Morris et al., 2003; Murdoch et al., 2007; Niethammer et al., 2000; Ogawa et al., 2005; Ozeki et al., 2003; Purohit et al., 1999; Sasaki et al., 2000; Sawamura et al., 2008; Sayer et al., 2006; Shinoda et al., 2007; Singh et al., 2010; Smith et al., 2000; Stehman et al., 2007; Sweeney et al., 2001; Tai et al., 2002; Takahashi et al., 2002; Taya et al., 2007; Toyo-oka et al., 2005; Wang et al., 2010).