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Online Discussions

Updated 14 January 2009
Printable version

Live Discussion: DISC1 Roundtable 2009

Akira Sawa

Nick Brandon

Ty Cannon

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.

View Transcript of Live Discussion — Posted 24 March 2009

View Comments By:
Barbara Lipska, Joel Kleinman — Posted 11 January 2009
Carsten Korth — Posted 11 January 2009
Anil Malhotra — Posted 12 January 2009
David J. Porteous — Posted 12 January 2009
David St Clair — Posted 12 January 2009
Steven Clapcote — Posted 12 January 2009
Mikhail Pletnikov — Posted 13 January 2009
Tatiana Lipina — Posted 16 January 2009
Jesus Requena — Posted 16 January 2009
Peter Penzes — Posted 19 January 2009
David J. Porteous — Posted 4 March 2009
Alexander Arguello — Posted 27 March 2009

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

Comments on Online Discussion
Comment by:  Barbara LipskaJoel Kleinman
Submitted 11 January 2009 Posted 11 January 2009

If indeed genetic variation in the DISC1 gene confers risk...  Read more

View all comments by Barbara Lipska
View all comments by Joel Kleinman

Comment by:  Carsten Korth, SRF Advisor
Submitted 11 January 2009 Posted 11 January 2009

This is my current view of DISC1-related research: ...  Read more

View all comments by Carsten Korth

Comment by:  Anil Malhotra, SRF Advisor
Submitted 12 January 2009 Posted 12 January 2009

DISC1 appears to be related to a number of psychiatric...  Read more

View all comments by Anil Malhotra

Comment by:  David J. Porteous, SRF Advisor
Submitted 12 January 2009 Posted 12 January 2009

I am unfortunately unable to attend the live discussion,...  Read more

View all comments by David J. Porteous

Comment by:  David St Clair
Submitted 12 January 2009 Posted 12 January 2009

I think that it has been a very productive couple of years...  Read more

View all comments by David St Clair

Comment by:  Steven Clapcote
Submitted 12 January 2009 Posted 12 January 2009

After much anticipation, a variety of mutant and...  Read more

View all comments by Steven Clapcote

Comment by:  Mikhail Pletnikov
Submitted 12 January 2009 Posted 13 January 2009

I have tried to answer some of the questions asked by the...  Read more

View all comments by Mikhail Pletnikov

Comment by:  Tatiana Lipina
Submitted 16 January 2009 Posted 16 January 2009

The study of Disc1's biological role gives us hope to...  Read more

View all comments by Tatiana Lipina

Comment by:  Jesus Requena
Submitted 15 January 2009 Posted 16 January 2009

I think that there is little doubt that DISC1 is a...  Read more

View all comments by Jesus Requena

Comment by:  Peter Penzes
Submitted 13 January 2009 Posted 19 January 2009

The number of publications on DISC1 has been rising...  Read more

View all comments by Peter Penzes

Comment by:  David J. Porteous, SRF Advisor
Submitted 4 March 2009 Posted 4 March 2009

The online DISC1 discussion organized by Akira Sawa, Nick...  Read more

View all comments by David J. Porteous

Comment by:  Alexander Arguello
Submitted 25 March 2009 Posted 27 March 2009

In reading the online DISC1 discussion, which I...  Read more

View all comments by Alexander Arguello
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