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

Posted on 22 Jan 2007
David Porteous Ishizuka et al. 2006 Porteous et al. 2006

The past year has seen a flurry of activityon both the experimental and speculative frontssurrounding 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 Gault"Posted 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

 

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?