The Sawa group have further expanded our knowledge of the complex existing between DISC1 and the molecule Nudel (Ndel1). They had already shown that the two molecules interact through the C-terminus of DISC1 (Ozeki et al., 2003), and in a 2005 Nature Cell Biology paper, they showed the critical role of the DISC1/Ndel1 complex as part of the dynein motor complex at the centrosome and showed that either loss of DISC1 through in utero RNAi, or by disruption of DISC1 function by overexpression of the truncated DISC1 protein, disrupts cortical migration (Kamiya et al., 2005; also see SRF related news story). In this study they have further refined the site of DISC1-Ndel1 interaction on DISC1 to amino acids 802-835 on DISC1. They have also confirmed that two amino acids on Ndel1 are essential for DISC1 binding (LE266/267) as previously published (Brandon et al., 2004), but they have now shown functional significance of this binding site through utilizing neurite outgrowth as a functional readout. RNAi depletion of Ndel1 inhibits neurite outgrowth, which is recoverable by overexpression of Ndel1 but not Ndel1 with the LE266/267AA mutation, which fails to bind DISC1. This shows how the DISC1-Ndel1 interaction is essential for neurite outgrowth.

Interestingly, Kamiya and colleagues have then gone on to look at the effects of known DISC1 variants on the interaction with Ndel1. They show that a splice variant of DISC1 (Δ22aa) has reduced binding, while the Ser704Cys polymorphism (Callicott et al., 2005) affects binding with the Cys variant having slightly stronger binding. This type of information is absolutely vital as we try to understand the relevance of the biology of DISC1 to the biology of schizophrenia and other psychiatric disorders. It is becoming evident that the complexities of the latter may be explainable by the complexities of the former. This has been further highlighted recently by the publication of the DISC1 interactome (Camargo et al., 2006) and the latest tranche of DISC1 data published at the SfN meeting in Atlanta (see SRF related SfN Atlanta story). What has really excited me, though, is the potential that DISC1 is interacting with other risk genes. For example, dysbindin and DISC1 have been suggested to share protein partners (Camargo et al., 2006) and DISC1 and PCM1 have been shown to bind directly (Kamiya et al., 2006; also see SRF related news story). The possibility that schizophrenia risk genes are potentially interacting in related complexes starts to allow the field to simplify its thinking and to focus hopefully on a few key pathways/processes as we look to develop both a better understanding of the disease and new therapeutics.

The DISC1 field faces a challenging period as we try to assimilate and understand, in the context of the disease, all the recent reports on protein interactions, cellular location, clinical relevance, etc. A combination of more refined cell biology and more relevant animal models will really help in this regard. A bona fide DISC1 knockout will go some way to help us here, as will the temporal and spatial understanding of the relevance of the DISC1 interactome (Camargo et al., 2006). It is going to be another exciting few years.

References:

Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B, Camargo LM, Oliver KR, Beher D, Shearman MS, Whiting PJ. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders.Mol Cell Neurosci. 2004 ;25(1):42-55. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia.Proc Natl Acad Sci U S A. 2005;102(24):8627-32. Abstract

Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry. 2006 Oct 17; [Epub ahead of print] Abstract

Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M, Cascio MB, Elashvili S, Koizumi H, Takanezawa Y, Dickerson F, Yolken R, Arai H, Sawa A. DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet. 2006;15(22):3313-23. Abstract

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 ;7(12):1167-78. Abstract

Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, Okawa M, Yamada N, Hatten ME, Snyder SH, Ross CA, Sawa A. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):289-94. Epub 2002 Dec 27. Erratum in: Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13969. Abstract

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