Chat leaders Akira Sawa of Johns Hopkins University, Nick Brandon of Wyeth Research, and Ty Cannon of UCLA led us in a wide-ranging discussion of all things DISC1 on January 13, 2009, including the following:
The molecular biology of DISC1 and its various isoforms.
Approaches to studying disruptions of the gene in rodents and other organisms.
The value of DISC1 in efforts to categorize and treat neuropsychiatric disease.
As we await the posting of the transcript, we invite you to read the background text and to offer your comments.
Background Text by Akira Sawa and Nick Brandon
It has been a very productive two years in the DISC1 area since the previous Schizophrenia Research Forum roundtable (see Porteous"s background text and Sawa"s post-meeting summary), and as the field is poised for its next batch of publications, especially in generation of model animals for DISC1 (Wang et al., 2008) and identification of molecular pathways involving DISC1 and other genetic risk factors (e.g., Kamiya et al., 2008; see SRF news story). Therefore, we believe that it is again a good time to get a group together to look at the progress that has been made and to make suggestions on areas in which we need to work harder.
Genetically, DISC1 is a major risk factor for a wide range of psychiatric disorders, including schizophrenia (Chubb et al., 2008). A rare variant with strong biological impact associated with the disorders in the DISC1 locus was identified from a large Scottish Pedigree (St. Clair et al., 1990). Some, but not all, association studies have supported that DISC1 is a risk factor for schizophrenia; nonetheless, such association becomes more promising when specific disease-related endophenotypes are considered (Cannon et al., 2005). It is still an excellent question as to what are the nature and effects of DISC1 variants in psychiatric genetics. This question is crucially associated with an issue of how we can utilize DISC1 genetically engineered organisms/animals in a translational sense.
From a biology viewpoint, DISC1 is a multifunctional protein localized to several distinct subcellular compartments (Ishizuka et al., 2006). DISC1 interacts with many proteins of importance (Camargo et al., 2007) and seems to function as an anchoring protein to regulate distinct cascades either at certain developmental time-points or in response to various stimuli. Thus, important questions in DISC1 biology are: what is the nature of disease-relevant DISC1 cascades or molecular pathways, and how are these cascades distinctly regulated in a context-dependent manner (e.g. temporally and spatially)? The complexity of DISC1 isoforms is still unsolved and could be critical for this last question. For example, when we consider the recently appreciated centrosomal and synaptic roles of DISC1, where does the underlying versatility derive from? Is it due to different DISC1 isoforms or due to the same species playing different roles at different developmental stages (or both)?
Based on this platform, the following points should be considered for this discussion.
1) The complexity of the DISC1 molecule (isoforms, potential role for antisense transcripts and fusion transcripts)
2) Understanding the cellular roles of DISC1 in partnership with other risk factors for schizophrenia (disease-associated molecular pathways/cascades) in context-dependent situations (cellular compartment, cell types, brain regions, developmental timing)
3) The role for model organisms (mice, flies, zebrafish, etc.) in DISC1 research, especially their translational utilities. With the burgeoning number of DISC1 mice, can we rationalize a path forward? Are all these models in all cases simply interfering with a key neurodevelopmental protein or are they really telling us something about the human disease? In terms of non-mouse models, what are we learning and does it have any relevance to humans?
4) Nature and effects of DISC1 variants on phenotypes/endophenotypes beyond DSM diagnostic criteria
5) Should we expect any therapeutic breakthroughs for schizophrenia and other neuropsychiatric disorders via DISC1 research?
Key papers to be read
1. St Clair DM, Blackwood DHR, Muir WJ, et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet (1990) 13-16. Abstract
2. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry . 2005 Nov 1 ; 62(11):1205-13. Abstract
3. Ishizuka K, Paek M, Kamiya A, Sawa A. A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. Biol Psychiatry . 2006 Jun 15 ; 59(12):1189-97. Abstract
4. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry . 2008 Jan 1 ; 13(1):36-64. Abstract
5. 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 . 2007 Jan 1 ; 12(1):74-86. Abstract
6. Kamiya A, Tan PL, Kubo K, Engelhard C, Ishizuka K, Kubo A, Tsukita S, Pulver AE, Nakajima K, Cascella NG, Katsanis N, Sawa A. Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Arch Gen Psychiatry . 2008 Sep 1 ; 65(9):996-1006. Abstract
7. Wang Q, Jaaro-Peled H, Sawa A, Brandon NJ. How has DISC1 enabled drug discovery? Mol Cell Neurosci . 2008 Feb ; 37(2):187-95. Abstract