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Online Discussions

Updated 14 January 2009 E-mail discussion
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 for mental illness, the effects of risk-associated polymorphisms should be detectable at the level of pre-mRNA processing, transcription, post-translational modification of proteins or their subcellular distribution, as these are the most proximal intermediate phenotypes to risk-associated alleles. So far, however, the results of studies searching for molecular correlates of genetic associations have been inconclusive and the mechanisms remain unknown. Although reduced expression of DISC1 mRNA was found in the lymphoblastoid cell lines of family members with the translocation (Millar et al., 2005) and in bipolar disorder patients with a putative risk haplotype (Maeda et al., 2006), no changes were detected in the brain tissue of unrelated patients with schizophrenia or in individuals carrying risk genotypes (  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:

What is the current situation in linking DISC1 to psychiatric disease?
1. There is the Scottish pedigree where DISC1 disruption could be genetically linked to clinical phenotypes of chronic mental diseases

2. Genetic association studies have associated polymorphisms within DISC1 to different psychiatric diseases but these results are sometimes weak and seem inconsistent

3. Animal models modeling the familial DISC1 mutation or other DISC1-related constructs consistently demonstrated behavioral changes, and in some models also subtle neuropathological ones (enlarged third ventricles, etc.).

What are the problems?
1. Does DISC1 have anything to do with sporadic cases of chronic mental disorder (CMD)?

2. If yes, what is the molecular mechanism of action?

3. Given the multitude of molecular interactions of DISC1, is there a smallest common molecular denominator of DISC1 dysfunction with regard to behavioral (or other) phenotypes?

General comments:
I agree that it is of...  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 phenotypes, bridging across traditional diagnostic boundaries and influencing key clinical manifestations of illness including neurocognitive function, symptom domains, and neuroimaging parameters. In addition, we (Burdick et al., 2008) and others have recently noted that the DISC1 interactome is also critically related to this broad array of phenotypes, and the specific genetic relationship may be predicated on different DISC1 genetic backgrounds. Therefore, the examination of single genes, and proteins, may not be sufficient to fully assess the biological effects of this system on behavioral phenotypes.

This complexity further complicates the search for relevant animal models, as most genetic models are based upon single gene perturbations. Animal models that incorporate perturbations across multiple genes and that can take into account developmental timing and produce relevant behavioral phenotypes would be a great step forward. In particular, the relationship of DISC1...  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, but I am pleased to note this topic being revisited. All of the evidence gathered since the last SRF discussion supports my view that the study of DISC1 genetics and biology has much to offer the field. I have followed each of the topic questions with a short comment. I hope you find these helpful and that the discussion is productive. Also, if you haven’t already done so, check out the SRF meetings calendar or go straight to the Keystone Meetings website and register for the following meeting. There is a great lineup of speakers, loads of discussion, plus fantastic snow sports.

Conference: The Molecular Basis of Schizophrenia and Bipolar Disorder
Date: 6-10 March 2009
Location: Keystone Resort, Keystone, CO, U.S.A.

1) The complexity of the...  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 since your last forum, and DISC1 has established itself as one of the most interesting genes in psychiatric genetics.

The recent work examining CNVs in schizophrenia over the last 12 months indicates 1) that there are likely to be very many other rare high penetrant mutations which, like DISC1 mutations, predispose individuals and families to high risk of schizophrenia and other neuropsychiatric disorders, and 2) that as with DISC1 there is unexpected clinical phenotypic diversity. Most of these CNVs, whether deletions or duplications, disrupt some or many aspects of CNS function at all stages of brain development. In some cases these mutations are so rare that it will be difficult to show statistical association with schizophrenia and evidence of involvement will need to be circumstantial. The great advantage of theDISC1 mutation is that so many members of the family with the mutation are affected that the association is highly unlikely to be due to chance.

Detailed study of all aspects of DISC1 is likely to...  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 transgenic DISC1 mouse lines from several research groups has been published over the last two years. Most of these attempt to mimic the original t(1:11) DISC1 mutation by transgenic expression of truncated DISC1 proteins. The Gogos group introduced a targeted premature stop codon into exon 8 of the endogenous DISC1 of the 129 mouse strain (Koike et al., 2006; Kvajo et al., 2008), which itself was found to carry a spontaneous premature stop codon in DISC1 exon 7 (Koike et al., 2006). The Pletnikov, Sawa and Silva groups generated transgenic lines that have constitutive (Hikida et al., 2007) or inducible (Li et al., 2007; Pletnikov et al., 2008) CaMKIIa promoter-driven expression of truncated human DISC1. The St Clair group generated a BAC transgenic...  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 discussants.

With the burgeoning number of DISC1 mice can we rationalize a path forward?

Combining available animal DISC1 models with other genetic mouse models and/or environmental factors appears as an obvious next thing to try to answer some fundamental questions about psychiatric disorders. Again, we will be using DISC1 as a great discovery tool.

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?

I would suggest both. In other words, by interfering with a key developmental protein, we are beginning to understand better the biology and functions of DISC1 and potential pathogenic process of psychiatric disorders when the functions are perturbed.

In terms of non-mouse models what are we learning and does it have any relevance to man?

I often feel that many investigators are either overly optimistic or too negative towards animal models. Models are just what they are—models....  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 comprehend much deeper neurobiological processes of such complex psychopathologies as schizophrenia or bipolar disorder. Analysis of Disc1 interactions with many other proteins (Camargo et al., 2007) will help us to dissect the function(s) of each molecular player. Excellent recent reviews by Chubb et al., 2008, and Wang et al., 2008, are very helpful in fully comprehending the biology of Disc1. I will give you some of my comments regarding the preliminary questions for the DISC1 roundtable discussion:

1. The complexity of the DISC1 molecule (isoforms, potential role for antisense transcripts and fusion transcripts). What is the role of multiple isoforms of Disc1? I think the comparison of Disc1 structure, functions between biological species from an evolutionary point of view, might be helpful at least to understand the origins of multiple Disc1 isoforms.

2. Understanding...  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 fantastic tool to probe the mechanism(s) underlying schizophrenia and mental disease in general, and I am convinced that many exciting breakthroughs lie ahead. However, I would like to share some cautioning thought, following up on comments from my colleague Carsten Korth: What if DISC1 has absolutely nothing to do with sporadic cases of mental disease (SMD), because it is upstream of the damage/alterations that occur in these diseases? For example, let´s suppose that DISC1, through its interaction with PDE4B, plays an essential regulatory role in the flow of cAMP to some specific cell location in a given set of neurons, in turn, that cAMP flow regulates the activity of a given effector, "X." Now let´s imagine that 99.9 percent of SMD is caused by a malfunction in X that is caused by an environmental stress (this is just for the sake of argument). DISC1 malfunction, by disrupting the "X route" upstream, would end up in mental disease, but studying the role of DISC1 in neurogenesis, or its interaction with NUDEL (again for the...  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 steadily and rapidly, from below 15 in 2004 to over 60 in 2008. This pace of discovery will certainly accelerate in the coming years. Light has been shed on many aspects of DISC1 molecular properties, expression, and functions. Mutant mice have been generated with different types of alterations in DISC1 function, and these mice have been analyzed for anatomical alterations, synaptic properties, cognitive functions, and other behaviors. New genetic studies further associated DISC1 with psychiatric disorders.

An important role in brain development for DISC1 acting at the centrosome has been established. Several of its protein interactors, also supported by recent studies, suggest other potential functions for DISC1, in other neuronal compartments. Of these, synaptic functions of DISC1 are particularly interesting, as synaptic dysfunction is thought to play an important role in psychiatric disorders. One good reason why it is worth examining plasticity related functions of DISC1 is because plasticity is ongoing throughout...  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 Brandon, and Ty Cannon and hosted by SRF on January 13, 2009, was certainly lively and nicely demonstrated how much the field has moved on since the first such discussion just two years earlier. Most gratifyingly, many new researchers have entered the fray with probing questions and fresh ideas.

If two years ago there was some lingering debate as to whether or not DISC1 was a bona fide genetic risk factor in schizophrenia, that is now well and truly settled in the positive. But the more interesting questions only partially addressed and answered in the discussion are what are the genetic mechanisms (haploinsufficiency, dominant negative), the genetic classes of variation (regulatory, copy number, missense) and their relative abundances, and what are their respective phenotypic effects at the molecular, cellular, neurological, and clinical levels? This to me is one of the main opportunities for the DISC1 field and the challenges to the rest of the field of biological psychiatry. Evidence is growing for both direct...  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 unfortunately missed, I saw there were many good points concerning DISC1 biology, but there are others that need to be emphasized. The discussion rightly pointed out that DISC1 is a complex gene with potentially many post-transcriptional and post-translational modifications. The group seemed to agree that the tools used to interrogate DISC1 function therefore need to be well calibrated and validated to insure reliability and replicability of any findings. This will be important for identifying which of the many DISC1 biological pathways are relevant to its role in disease risk. This in and of itself is not an easy task, but suggestions are offered below.

The recent past in human genetics and animal models have taught us that translating common genetic variation (e.g., SNPs) into valid animal models is highly difficult. Even if unequivocal risk SNPs are identified for a given locus (to date, this seems not to be the case), the functional effects of those SNPs may be difficult to determine. It is therefore not possible to...  Read more

View all comments by Alexander Arguello
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