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Updated 3 January 2007 E-mail discussion
Printable version

Live Discussion: The DISC1 Pathway in Major Mental Illness: Clinical, Genetic and Biological Evidence—Current Status and Future Prospects

David Porteous

Ishizuka et al. 2006

Porteous et al. 2006

The past year has seen a flurry of activity—on both the experimental and speculative fronts—surrounding disrupted-in-schizophrenia 1 (DISC1). To help make some sense of the recent studies and reviews, David Porteous of the University of Edinburgh helped us convene a virtual “roundtable” on the topic on January 23, 2007. If you missed the discussion, we invite you to read the background text below, not to mention the suggested articles (at left), comments left before the chat, and especially, the chat transcript.

Any comments you contribute to this discussion will appear in our What's New section and in our newsletter (See also the SRF news stories mentioned in the text below, as well as an SRF meeting report on DISC1 presentations at the Neuroscience 2006 meeting).

Special Update: Following the posting of the transcript, we asked Akira Sawa of Johns Hopkins University, who was unable to join us for the live chat, to serve as a discussant. He obliged by reviewing some of the interesting discussion, as well as mentioning questions that were not brought up. Please read his review.

Our thanks to Biological Psychiatry and Elsevier for granting open access to these two papers:

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

View comments by:
Judith GaultPosted 23 January 2007

Porteous DJ, Thomson P, Brandon NJ, Millar JK. The genetics and biology of DISC1--an emerging role in psychosis and cognition. Biol Psychiatry. 2006 Jul 15;60(2):123-31. Abstract

View Transcript of Live Discussion — Posted 25 February 2007

View Comments By:
Akira Sawa — Posted 16 January 2007
Mikhail Pletnikov — Posted 19 January 2007
Nick Brandon — Posted 19 January 2007
Christopher Ross — Posted 20 January 2007
Chris Carter — Posted 20 January 2007
David J. Porteous — Posted 23 January 2007
Katherine E. Burdick — Posted 23 January 2007
John Roder — Posted 23 January 2007
Akira Sawa — Posted 16 March 2007

Background Text
By David Porteous

The purpose of this forum is to discuss recent clinical, genetic, and biochemical evidence linking DISC1 and DISC1 interactors to susceptibility to major mental illness (see recent reviews by Ishikura et al. (2006), Biological Psychiatry, 59, 1189-1197; Porteous et al. (2006); and Porteous and Millar (2006)).

DISC1 was discovered as a novel gene at the breakpoint on chromosome 1q42 in a single Scottish family in which a balanced translocation between chromosomes 1 and 11 co-segregates with major mental illness, diagnosed as schizophrenia, bipolar disorder, or recurrent major depression. Recently, a number of independent genetic studies in various populations have implicated the DISC1 locus by linkage or association for schizophrenia, schizoaffective disorder, bipolar disorder, and major depression. Other studies of clinical and normal variation in measures of cognition and brain structure and function have also implicated a role for DISC1.

In parallel, our knowledge and understanding of DISC1 has increased (see SRF related news story). DISC1 is widely expressed, but developmentally regulated, with high levels of brain expression during prenatal neurogenesis and in the adult hippocampus. Downregulation of Disc1 expression by RNAi in the mouse neonate has been reported to result in abnormal neuronal migration and arborization. The 129 strain of mouse has a mutant form of Disc1, and this is associated with a deficit in working memory (see SRF related news story).

There is now a large body of direct evidence to show that DISC1 acts as a “hub” or scaffold protein, interacting with multiple protein partners, several of which are already known to play important roles in neurodevelopment, neurotransmission and signaling, the cytoskeleton, and centrosomal function.

The purpose of this forum is to review the current data, identify gaps or ambiguities in the current evidence, consider some unanswered questions of immediate relevance to the field, and discuss how these might best be addressed by prospective studies.

Some provisional questions:

1. What are the nature and effects of DISC1 mutations?
2. How is DISC1 expression regulated?
3. What are the consequences of aberrant DISC1 expression at the cellular and developmental level?
4. How, when, and where is DISC1 expression altered in the brains of subjects with mental illness?
5. What is the role of DISC1 in determining brain development?
6. What is the mechanism for DISC1 regulating cognitive processes, learning, and memory?
7. Can mouse models of the DISC1 pathway provide developmental and mechanistic insights not possible in patient studies? 8. Does DISC1 identify a target pathway for rational drug development in the treatment of psychosis and mood disorder?

Comments on Online Discussion
Comment by:  Akira Sawa, SRF Advisor
Submitted 16 January 2007 Posted 16 January 2007

I have been impressed by the recent paper in Molecular Psychiatry (Camargo et al., 2006), exploring molecular networks involving DISC1.

Exploration of in vivo models is very important (having several different types of DISC1 animal models will be important), provided that the underlying mechanisms of genetic manipulations in mice are clarified in cell biology first.

View all comments by Akira Sawa

Comment by:  Mikhail Pletnikov
Submitted 19 January 2007 Posted 19 January 2007

I sometimes cannot help thinking that without DISC1 we would still have been hunting for additional subtypes of 5-HT or DA receptors to provide more targets for fine tuning of neuronal functioning. It seems that DISC1 and a few other genetic risk factors, e.g., neuregulin, are finally pulling the research in mental illnesses away from the simplistic classical psychopharmacology toward the realm of cellular neurobiology. The recent publications by several groups have clearly demonstrated this point. However, a nagging feeling is emerging that the picture is going to have to be even more complicated than just 7 or 8 subtypes of 5-HT receptors. We are going to have to think in the terms of systems analysis. The entire biology and entire interactome of the neuron has to be considered to understand the role(s) of DISC1. In this context, I would like to comment on two questions put forward by Dr Porteous.

I would be inclined to be a bit more cautious with “the mechanism for DISC1 regulating cognitive processes, learning, and memory" (question 6). DISC1 is unlikely to regulate...  Read more

View all comments by Mikhail Pletnikov

Comment by:  Nick Brandon (Disclosure)
Submitted 19 January 2007 Posted 19 January 2007

It's an exciting time for research around DISC1. There is real momentum in the field which is culminating in some really beautiful cell biology studies as seen by the recent manuscripts in the Journal of Neuroscience (see SRF news story) and going back further to the Kamiya paper in 2005 in Nature Cell Biology (see SRF news story). As Akira has commented already, the exploration of animal models is crucial to the field. We must be careful in this regard though—The relevance of the mutations or pertubations must be considered very carefully. DISC1 has really opened up some very attractive areas of cell biology to be explored for schizophrenia and I look forward to a discussion on how we develop these further.

View all comments by Nick Brandon

Comment by:  Christopher Ross
Submitted 20 January 2007 Posted 20 January 2007

DISC1’s increasingly extensive interactome and rich cell biology, combined with the rapidly developing genetics (e.g., comment above by Brandon and links within, and the studies of Craddock’s group—e.g., Hamshere et al., 2005) suggest that DISC1 has the potential to be a kind of “Rosetta stone” for psychiatric genetics—helping us both to uncover pathogenic pathways and also to reconceptualize phenotypes.

Some hypotheses: pathways involving proteins (e.g., NudEL or PCM1) at the centrosome or motor proteins involved in nucleokinesis may lead to developmental phenotypes most like deficit schizophrenia; pathways involving proteins potentially regulating synaptic plasticity may lead to phenotypes most like schizophrenia and schizoaffective disorder; and pathways with proteins (e.g., PDE4B) involved in neurotransmission and neuromodulation may lead to phenotypes most like affective disorder (see also Ross et al.,...  Read more

View all comments by Christopher Ross

Comment by:  Chris Carter
Submitted 20 January 2007 Posted 20 January 2007

DISC1 as a Hub Gene

Camargo and colleagues, in their DISC1 and dysbindin interactome study, have emphasised the convergence of schizophrenia risk genes on common biological processes(Camargo et al., 2007) (see also SRF news story).

I thought it might be interesting, for this roundtable, to take this a step further and see whether the DISC1 binding partners interact with other schizophrenia or bipolar susceptibility candidates. This is not a fully referenced or in depth analysis and is taken primarily from the interaction section of the ENTREZ gene data for each DISC1 binding partner.

DISC1 binds directly to six other genes implicated in schizophrenia or bipolar disorder (CIT, DPYSL2, FEZ1, MLC1, NDE1, PDE4B) and can be linked in two steps to many other susceptibility candidates, related in particular to glutamate and growth factor signalling, axonal transport and other processes, including those controlled by...  Read more

View all comments by Chris Carter

Comment by:  David J. Porteous, SRF Advisor
Submitted 23 January 2007 Posted 23 January 2007

Several of you have posted interesting comments which I hope we can pick up on later today. A brief summary of some of the key points would be: what can we learn about DISC1 function from a systems approach; what might be the strengths and possible limitations of mouse models; is there allelic heterogeneity at the DISC1 locus and how might we predict that this would be reflected in the clinical phenotype? Recent papers by Hennah et al, Carmargo et al, Taya et al and Shinoda el al have raised interest. Read Tom Fagan's excellent summary on the Forum website. Go to Carter's web site for his view of the DISC network. Talk to you later.

View all comments by David J. Porteous

Comment by:  Katherine E. Burdick
Submitted 23 January 2007 Posted 23 January 2007

There has been a growing interest in the DISC1 gene, as convergent evidence suggests that it acts to influence a number of clinical traits including susceptibility to a range of psychiatric illnesses, cognition, brain morphology, and positive symptoms. These broad-ranging effects suggest that its action may be mediated by multiple loci within the gene via differential effects on expression, in addition to complex interactions among DISC1 and its multiple confirmed binding partners (Porteous et al. 2006).

Several recent studies have begun to elucidate the functional biology of the DISC1 protein and its binding partners, particularly with regard to NUDEL: a) The enzyme activity of NUDEL is inhibited by DISC1 (Hayashi et al. 2005) b) NUDEL expression is reduced in hippocampus of patients with schizophrenia and DISC1 risk alleles predict reduced expression of NUDEL (Lipska et al. 2006); c) The intact interaction between DISC1 and NUDEL is necessary for neurite outgrowth (Kamiya et al. 2006) and other key neurodevelopmental processes (Taya et al. 2007) that are known to be...  Read more

View all comments by Katherine E. Burdick

Comment by:  John Roder
Submitted 23 January 2007 Posted 23 January 2007

Being newcomers to the field, we reviewed it a few years ago and decided that DISC1 was the best candidate gene for schizophrenia and/or mood disorders, based on the co-segregation of these diseases with a chromosomal translocation disrupting DISC1 in a large Scottish family. Reciprocal translocations have led to great strides in the cancer area. For example, translocations sometimes activate human oncogenes leading to tumors in humans. Conventional association studies in people do not have the resolving power to yield single genes. Also the DISC1 association held up, not only in the original Scottish family, but also in other populations throughout the world. Although there are many other candidate genes, we found the evidence for DISC1 to be overwhelming (see featured reviews). The only missing data would be to show DISC1 perturbations in mice caused a partially overlapping phenotype to humans.

We set up assays of behavioural endophenotypes for some shared “traits.” We were able to establish assays for sensorimotor gating (pre-pulse inhibition of the acoustic startle),...  Read more

View all comments by John Roder

Comment by:  Akira Sawa, SRF Advisor
Submitted 16 March 2007 Posted 16 March 2007

On behalf of all the investigators who believe DISC1 is a promising lead to understanding the molecular pathology of major mental illnesses, I would like to say thank you very much to Hakon Heimer and David Porteous for planning and organizing this roundtable discussion. Here, I would like to review the DISC1 research based on the fruitful discussions in the roundtable. The following subjects will be covered in this overview:

1. Clinical Subtypes and Biological Pathways Involving DISC1
2. DISC1 Isoforms
3. DISC1 Animal Models
4. DISC1: Potential Target for Therapeutic Strategies?

Of note, many basic neuroscientists (not scientists primarily working on psychiatric disorders), especially those who are interested in synaptic plasticity and brain development, are currently interested in DISC1. This trend was not well covered in the roundtable discussion (see, e.g., the work by Kozo Kaibuchi's group, discussed in Tom Fagan's SRF article).

1. Clinical Subtypes and Biological Pathways...  Read more

View all comments by Akira Sawa
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