Trends in Molecular Medicine
Disrupted in schizophrenia 1: building brains and memories
Section snippets
Mental illness – who gets it and why?
What do the actress Veronica Lake, the mathematician John Nash and the blues guitarist Peter Green have in common? And the politician Winston Churchill, the astronaut Buzz Aldrin and the author Virginia Wolff? The answer is that the first group had been diagnosed with schizophrenia, whereas the second group with bipolar disorder (http://en.wikipedia.org/wiki/Mental_illness and http://www.mental-health-today.com). There has been a long-standing link between genius, creativity and madness [1],
Discovery of DISC1
Despite the evidence for a substantial genetic contribution to the risk of developing SCZ and BPAD, the discovery of the genes that are involved in these disorders has not been easy. This reflects in part the problems and limitations of clinical diagnosis and the diagnostic boundaries. Unlike other complex genetic disorders such as cancer, heart disease or diabetes, there are no reliable biological markers of risk or disease, and there is limited access to affected tissues. This and the fact
Genetic evidence
In addition to DISC1, DISC2 is also directly disrupted by the t(1;11) translocation [7]. This gene is located antisense to DISC1 and, because there are no identifiable open reading frames, it might be an RNA transcript that regulates DISC1 expression. Moreover, as with any chromosomal rearrangement it is possible that expression of genes in close proximity to the t(1;11) chromosomal breakpoints might be altered. Thus, independent genetic evidence is crucial to establish the role of DISC1 as a
The function of DISC1 and of DISC1 interacting proteins
The gene sequence and genomic structure of DISC1 are conserved across primates, rodents and the compacted vertebrate genome of the pufferfish [31]. DISC1 is expressed in multiple isoforms and the pattern of expression is cell-type-specific 32, 33, 34, 35. Expression is widespread, developmentally regulated and high in regions of the brain that are implicated in SCZ, most notably the hippocampus [36]. The protein sequence of DISC1 gave one clue to function – that is, the multiple putative
The cellular mechanism of DISC1 in building brains and memories
The evidence from t(1;11)-translocation-derived cell lines [8] is that there is a 50% reduction of the normal level of DISC1, which is indicative of an haploinsufficiency model. Consistent with this, Sawa and colleagues [9] have used RNA interference (RNAi) to downregulate endogenous DISC1 expression. These authors have shown that DISC1 has an important role in neuronal cell migration and neurite extension, which is consistent with the neurodevelopmental hypothesis for SCZ. They also
The need for (and role of) clinical studies
It is possible that variation in the human DISC1 gene will improve upon understanding how this relates to both normal and abnormal brain development and cognition. The DISC1 promoter and other putative regulatory domains are not well examined or screened for possible functional variants. This is a big gap that needs to be filled by replication and validation studies. Similarly, linkage, association, mutation and expression studies are also needed to assess whether molecules that interact with
The need for (and role of) animal models
From what has been said earlier, it is clear that animal models for psychiatric disorders would be valuable. Kioke et al. [52] recently reported that the 129S6/SvEv strain of mouse carries a 25bp deletion in exon 7 of Disc1. By marker-assisted backcrossing of 129S6/SvEv mice to the C57BL/6J strain, Kioke et al. [52] tested the effect of the 129 Disc1 variants on a C57 background and compare this with that of normal C57 mice. They reported a statistically significant deficit in working-memory
Prospects for rational drug development
The DISC1–PDE4B interaction is an obvious and primary target for the development of novel drugs. The current presumption is that cAMP is key to the morbid effect of haploinsufficiency for DISC1 or PDE4B, but whether modulation of cellular cAMP in the brain is sufficient and necessary for therapeutic benefit remains to be determined. Fortunately, the phosphodiesterases are already well-established drug targets in relation to vascular [53] and inflammatory diseases [54], and to cognitive
Conclusions
In summary, over the past 5 years, DISC1 has changed rapidly from a gene of direct relevance to vulnerability of major mental illnesses in a single, large Scottish family (but of uncertain wider relevance) to one of the most promising genes in the field. This family and subsequent DISC1 linkage and association studies also lend strong support for the growing notion that SCZ, BPAD and related mood and psychotic disorders might share common aetiological factors. This indicates the need for a move
Acknowledgements
This work was supported in part by the UK Medical Research Council. J.K. Millar is an RCUK fellow. The authors thank S. Cooper for artwork.
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