Review TRENDS in Molecular Medicine
6 June 2006
Disrupted in schizophrenia 1: building
brains and memories
David J Porteous and J Kirsty Millar
Medical Genetics Section, Edinburgh University Centre for Molecular Medicine, Western General Hospital Campus, Crewe Road,
Edinburgh EH4 2XU, UK
Schizophrenia and bipolar affective disorder are com-
mon, debilitating, and poorly understood and treated
disorders. Both conditions are highly heritable. Recent
genetic studies have suggested that the gene disrupted
in schizophrenia 1 (DISC1) is an important risk factor.
DISC1 seems to have a key role in building the brain and
memories by interacting with other proteins, including
nuclear distribution E-like protein and phosphodiester-
ase 4B. Here, we review the current knowledge, high-
light some key unanswered questions and propose
ways forward towards a better understanding of normal
and abnormal brain development and function. In the
long term, this might lead to the discovery of drugs that
are more efficacious and safer than currently available
ones.
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], but this hides a personal, familial, social
and economical burden of huge proportions [2] (http://
www.mentalhealth.org.uk). The list of famous people that
are affected by either schizophrenia or bipolar disorder is
long, but what about the millions of anonymous patients?
One in 50 individuals is affected by one or the other
disorder in their lifetime. Schizophrenia (SCZ) and bipolar
affective disorder (BPAD) are ranked 9th and 6th in the
World Health Organization (WHO) estimates for disease-
related lifetime disabilities [3]. The clinical management
of SCZ a major form of psychosis and bipolar affective
disorder a major mood disorder was revolutionised by
the introduction of anti-depressants and anti-psychotics in
the 1950s. These drugs target the monoamine, serotonin
and dopamine pathways, but cause unacceptable side
effects in some patients. Moreover, w30% patients do not
respond to these drugs and their overall efficacy is poor
(http://www.mentalhealth.org.uk). The available evidence
Corresponding author: Porteous, D.J. (david.porteous@ed.ac.uk).
Available online 6 May 2006
www.sciencedirect.com 1471-4914/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2006.04.009
Vol.12 No.
does not support the idea that these drug targets are the
causes of psychosis or mood disorder [2,4].
There is a substantial scientific literature on the signs,
symptoms and treatment of these disorders, and an
equally large non-scientific and, at times, conflicting
literature [1,2,4,5]. From the available data, it might be
inferred that we are still some way from a comprehensive
understanding of the causes and the biological nature of
these conditions. Without this knowledge, rational treat-
ment is just a faint hope. However, there might be some
hope on the horizon. Population, family and twin studies
have demonstrated the high heritability of both SCZ and
BPAD [6]. However, these are complex genetic conditions;
several different genetic factors of various strength and
frequency within a population are involved in different
individuals. Here, we focus on the protein disrupted in
schizophrenia 1 (DISC1) [7], and on some of its protein
partners [8,9] that are possibly the most-promising
candidates for SCZ to date [10].
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 that there are only few
clues of which genes might be responsible for these brain
disorders make the conventional strategies of family-
based genetic linkage (i.e. looking for genetic markers that
track with disease or disease risk) and population-based
association mapping (i.e. looking for gene variants that
are observed more often in affected or at risk individuals
than in matched controls) fraught with difficulties.
Molecular cytogenetics is a powerful alternative genome-
wide strategy to discover candidate genes in individuals
and families. Microscopically detectable cytogenetic
variants (duplications, insertions and/or deletions, inver-
sions or balanced translocations) are more common than
they were thought to be, affecting 12% of normal
newborns [11]. A recent spate of studies has also high-
lighted the extent of sub-microscopic copy-number vari-
ation (insertions or deletions that are large enough to
encompass whole genes) in the human genome [1214].
256 Review TRENDS in Molecular Medicine Vol.12 No.6 June 2006

High-resolution fluorescence in situ hybridisation,
competitive genome hybridisation and related-gene chip
differential hybridisation strategies can all detect cyto-
genetic variations with high sensitivity and specificity
[1517]. The underlying supposition is that, in an affected
individual (and any relatives who inherit the same lesion),
the cytogenetic event is necessary and sufficient to
predispose to the observed psychiatric diagnosis. This is
how both DISC1 [7] and its partner phosphodiesterase 4B
(PDE4B) [8] have been identified as candidate genes for
important mental illnesses.
St Clair et al. [18] showed that a Scottish family that
had a high incidence of psychiatric illnesses co-segregated
in a statistically significant way with a balanced trans-
location between chromosome 1 and chromosome 11
[logarithm of the odds (LOD) Z3.4]. In a follow-up study,
Blackwood et al. [19] reported that, of 29 individuals on
whom cytogenetic analysis had confirmed the presence of
the translocation, seven had a diagnosis of SCZ, one of
BPAD and ten of recurrent major depression (MDD).
Thus, 18 of 29 translocation carriers (62%) had a diagnosis
of a serious mental illness, whereas none of the 38 non-
translocation carriers had such a diagnosis, reinforcing
the evidence for causality (LOD Z7.1). Blackwood et al.
[19] also reported that the latency and amplitude of the
P300 event-related potential (ERP), an electrical brain
signal evoked by auditory stimulation, were reduced in
both affected and unaffected translocation carriers. Also,
as a group, the translocation carriers had the charac-
teristic abnormal ERP P300 that is associated with SCZ
and BPAD. Thus, the pattern of inheritance of SCZ and
affective disorders in the family with t(1;11) translocation
is consistent with a simple dominant mode of inheritance
with reduced penetrance, and with altered ERP P300 as a
possible correlated endo-phenotype. Millar et al. [7]
positionally cloned the translocation breakpoints and
identified the novel, large, multi-exon and multiple-
isoform gene DISC1 on chromosome 1.
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 susceptibility factor for psychiatric illnesses. This
evidence has come from linkage studies of Finnish,
Taiwanese, North American, Icelandic and British popu-
lations, using phenotype models that include SCZ, schizo-
affective disorder, BPAD and MDD [10,20,21]. Several
non-synonymous amino acid changes in DISC1 have been
described [22], and a common Ser764Cys variant has been
reported to be associated with SCZ, hippocampal develop-
ment and function [23] and also sex-specific cognitive
change that occurs with ageing in the normal population
[24] (Figure 1). Single nucleotide polymorphisms (SNPs)
that span the full genomic structure of DISC1 have also
been examined, and several positive disease associations,
both genotypic and haplotypic, have been reported from
Finland [25,26], North America [27] and Scotland [20].
There is evidence that DISC1 is also associated with visual
and working memory [26,28,29]. Therefore, the emerging

NLS
MPGGGPQGAP AAAGGGGVSH RAGSRDCLPP AACFRRRRLA RRPGYMRSST GPGIGFLSPA
VGTLFRFPGG VSGEESHHSE SRARQCGLDS RGLLVRSPVS KSAAAPTVTS VRGTSAHFGI
N-terminus

QLRGGTRLPD RLSWPCGPGS AGWQQEFAAM DSSETLDASW EAACSDGARR VRAAGSLPSA

S/F
ELSSNSCSPG CGPEVPPTPP GSHSAFTSSF SFIRLSLGSA GERGEAEGCP PSREAESHCQ PDE4
R
SPQEMGAKAA SLDGPHEDPR CLSQPFSLLA TRVSADLAQA ARNSSRPERD MHSLPDMDPG
NLS
SSSSLDPSLA GCGGDGSSGS GDAHSWDTLL RKWEPVLRDC LLRNRRQMEV ISLRLKLQKL

QEDAVENDDY DKAETLQQRL EDLEQEKISL HFQLPSRQPA LSSFLGHLAA QVQAALRRGA

L DISC1
TQQASGDDTH TPLRMEPRLL EPTAQDSLHV SITRRDWLLQ EKQQLQKEIE ALQARMFVLE
A K D Q Q L R R E I E E Q E Q Q L Q W Q GCDLTPLVGQ LSLGQLQEVS KALQDTLASA GQIPFHAEPP FEZ1
C-terminus

ETIRSLQERI KSLNLSLKEI TTKVCMSEKF CSTLRKKVND IETQLPALLE AKMHAISGNH

Breakpoint
F W T A K D L T E E I R S L T S E R E G L E G L L S K L L V L S S R N V K K L G S V K E D Y N R L R R EVEHQETAY
S
ETSVKENTMK YMETLKNKLC SCKCPLLGKV WEADLEACRL LIQCLQLQEA RGSLSVEDER
Q
QMDDLEGAAP PIPPRLHSED KRKTPLKVLE EWKTHLIPSL HCAGGEQKEE SYILSAELGE
LIS1
KCEDIGKKLL YLEDQLHTAI HSHDEDLIQS LRRELQMVKE TLQAMILQLQ PAKEAGEREA
AASCMTAGVH EAQA NDEL1
TRENDS in Molecular Medicine

Figure 1. DISC1 domain structure and interaction sites. Amino acid sequence of DISC1: the N-terminal and C-terminal portions are indicated on the left hand side of the figure.
A SerPhe rich domain (S/F) of unknown function is boxed and shaded in green, and putative nuclear localisation signals (NLS) are indicated in red. Motifs which might be
crucial for proteinprotein interactions include: (i) two proline-rich sequences (underlined in red): (ii) five coiled-coil domains (in bold); and (iii) leucine zipper regions
(underlined in black). The four known amino acid polymorphisms are indicated (the less-common amino acid is boxed and written in red above the consensus sequence). A
vertical red line marks the t(1;11) translocation breakpoint. Superimposed are the binding regions as best currently defined for the DISC1-interacting proteins PDE4 (blue),
FEZ1 (yellow), LIS1 (pink) and NDEL1 (green), plus the DISC1 self-interaction site (grey). DISC1 amino acids 598696 have also been suggested to be important for NDEL1
binding [37].

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 Review TRENDS in Molecular Medicine
Box 1 Outstanding questions
What are the nature and the effects of DISC1 mutations?
How is DISC1 expression regulated?
What are the consequences of aberrant DISC1 expression at the
cellular and developmental level?
How, when and where is DISC1 expression altered in the brains of
subjects with mental illnesses?
What is the mechanism by which DISC1 determines brain
development?
What is the mechanism by which DISC1 regulates cognitive
processes, learning and memory?
Can mouse models of DISC1 provide developmental and
mechanistic insights that cannot be obtained in patient studies?
Can DISC1 help in the identification of a target pathway for
rational drug development in the treatment of psychosis and
mood disorder?
picture is that of genetic variation in DISC1, possibly
mediated by multiple-risk haplotypes, conferring suscep-
tibility to SCZ and affective disorders, and also to altered
cognition in normal and affected subjects. These results,
although supporting a role for DISC1 genetic variation in
conferring susceptibility to SCZ and affective disorders,
need to be interpreted with some caution because
published studies have compared various phenotypes
and tested only partially overlapping sets of sequence
variants. Direct replication studies and a formal identifi-
cation of clear-cut functional variants are required.
Determining the normal function of DISC1 and disease-
associated variants is the obvious next step. Do common
variants of DISC1 affect normal processes of brain
development and function? Are these same common
variants also associated with major mental illnesses,
perhaps as a result of interaction between DISC1 and
secondary genetic or environmental factors? Or, does
DISC1 have multiple, independent mutations and pheno-
typic heterogeneity similar to those in genes that regulate
the level of high-density lipoprotein C [30]? Given the
evidence that DISC1 has a role both in brain development
and in neuronal function, it will be interesting to see how
and whether these different aspects relate to different
functional protein domains and patient phenotypes.
Moreover, given the evidence for multiple, independent
(or possibly co-dependent) protein binding domains, one
can speculate that the functional consequences of non-
synonymous amino acid variants or splice variants might
affect only a subset of DISC1 variants, whereas mutations
that lead either to alterations in DISC1 expression per se
or protein stability might have more pleiotropic and
pervasive effects (Box 1).
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 [3235]. 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 coiled-coil domains in its carboxy end are likely to
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Vol.12 No.6 June 2006 257
interact with other proteins. Over 50 putative DISC1
interacting proteins have been reported, several of which
have been confirmed in vivo [8,32,33,3741]. These
include PDE4B, nuclear distribution E-like (NDEL1,
also known as NUDEL), lissencephaly 1 (LIS1) and
fasciculation and elongation protein zeta-1 (FEZ1)
(Figures 1,2). The known or conjectured functions of
these DISC1 partners collectively suggest that DISC1 is
important for neuronal migration, cytoskeletal function
and neuronal signalling [36]. However, important ques-
tions remain: which isoforms of DISC1 bind to which
proteins? In what combination? And where in the cell do
these interactions occur? (Box 1).
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 neuro-
developmental hypothesis for SCZ. They also demonstra-
ted that, in rat PC12 cells, DISC1 co-immunoprecipitated
dynactin, dynein, g-tubulin, LIS1 and NDEL1. LIS1 and
NDEL1 are important in neuronal migration and neurite
outgrowth [42,43]. Their data also suggest that DISC1
stabilizes the dynein motor complex at the centrosome,
and this effect is destabilized by either RNAi-mediated
downregulation of DISC1 or by overexpression of a
truncated form of DISC1, which was designed to mimic
the putative product of the t(1;11) chromosome. There is
evidence that NDEL1 and LIS1 interact with DISC1
[9,39]. Several studies [32,33,35,37,39,40,44] reported
that DISC1 localises to the centrosome when it is
overexpressed, but Kamiya et al. [9] made a strong claim
that this is also true for endogenous DISC1. Millar et al.
[8] have shown no evidence for a stable, truncated DISC1
protein product from the t(1;11) chromosome. This is in
agreement with the findings of Kamiya et al. [9], who used
co-immunoprecipitation studies to show that DISC1 self-
associates through a domain proximal to where the t(1;11)
breakpoint falls (Figure 1). Thus, it can be predicted that
artificial truncated DISC1 constructs will self-associate
with and, therefore, deplete full-length DISC1, thus
explaining the similarity in cellular phenotype to that
observed using RNAi.
To test for effects of reduced full-length DISC1 protein
in vivo, Kamiya et al. [9] electroporated mouse cells in
utero at E14.5 with DISC1 RNAi molecules and truncated
DISC1 transgene. The electroporated cells were marked
with a green fluorescent dye. By comparing the position
and orientation of the fluorescent cells with the non-
electroporated neighbours, Kamiya et al. [9] demonstrated
that depletion of DISC1 inhibited neuronal migration in
the intermediate and subventricular zone, the ventricular
zone and the cortical plate. This was observable at P2. At
P14, a measurable reduction in the number and orien-
tation of dendrites was observed. The evidence that DISC1
258 Review TRENDS in Molecular Medicine
PDE4B
Catalytic unit
low activity
Memory building
FEZ1
DISC1
Figure 2. DISC1. The figure illustrates the key roles suggested for DISC1 in brain development through interaction with NDEL1, LIS1, FEZ1 and other co-complexing proteins,
and in cognitive processes that are involved in learning and memory through interaction with PDE4B to regulate cellular cAMP signalling. This figure is adapted in part from
Millar et al. [8].
has an important role in building the brain (Figure 2)
deserves further work to determine the functional
complex, mechanism and cell-signalling processes
involved (Box 1).
The clinical cue that DISC1 also has a role in building
memories (Figure 2) comes from genetic studies that point
to associations with various cognitive phenotypes. The
molecular clue comes from the discovery that PDE4B is
another candidate gene that is emerging from the strategy
of screening for cytogenetic rearrangements in probands
with SCZ or BPAD. A balanced t(1;16)(p31.2;q21) trans-
location in a patient with SCZ and in the cousin with a
psychotic disorder was identified, and the chromosome-1
breakpoint was shown to disrupt PDE4B [8]. PDE4B
belongs to the PDE4 family (PDE4A, PDE4B, PDE4C and
PDE4D) of phosphodiesterases, which are orthologous to
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Vol.12 No.6 June 2006
PDE4B
Catalytic unit
high activity
LIS1
NDEL1
Brain building
TRENDS in Molecular Medicine
the Drosophila learning and memory gene dunce [45].
PDE4 proteins are inhibited by the antidepressant drug
rolipram [46]. Moreover, mice with targeted disruption of
PDE4B and PDE4D behave like normal mice that have
been administered antidepressants [46,47]. Phosphodi-
esterases are the only means of inactivating cyclic AMP
(cAMP), which is a key signalling molecule involved in
learning, memory and mood [48,49]. Deficits of cAMP are
a prominent characteristic of SCZ. Similar to DISC1,
PDE4B is a convincing genetic and functional candidate
for psychiatric illnesses, and its candidacy will be proved
or disproved by future genetic studies of several
populations.
Intriguingly, PDE4B and DISC1 were found to be
binding partners; this molecular association might be
crucial to the aetiology of severe psychiatric illnesses [8].
 Review TRENDS in Molecular Medicine
Millar et al. [8] has shown that the binding of PDE4B to
DISC1 is highly dynamic, with cAMP upregulation
causing protein-kinase-A (PKA)-dependent dissociation
of PDE4B from DISC1, and a concomitant PDE4B
phosphorylation and activation. The hypothesis is that
DISC1 binds to an unphosphorylated low-activity form of
PDE4B that is released as a PKA-phosphorylated high-
activity form in response to cAMP upregulation. Millar
et al. [8] speculated that DISC1 acts as a molecular
scaffold, forming a complex with PDE4B in specific
subcellular compartments and sequestering it in a low-
activity form until it is needed to switch off cAMP
signalling. Consequently, DISC1 and PDE4B are likely to
function in tailoring cellular responses to cAMP, and this
interaction is, thus, expected to be crucial to CNS function.
It will be important to determine in which cells types
and where within the cells DISC1 and its protein partners
associate (Figure 1), and what effect binding of one protein
has on the other. It might be expected that protein-
interaction-induced conformational change might pro-
mote or inhibit binding of other partners. The isoform
specificity and dynamics of this process are important
questions that need to be addressed. Also, the effect of risk
haplotypes on either the quantity or the types of DISC1
isoforms, and the effect of sequence variants on DISC1
stability and function per se and of protein-binding
coefficients need to be addressed. The multiplicity of
DISC1 functions and the potential for phenotypic vari-
ation at the level of the neuron and of the brain provides a
possible explanation for the associated phenotypes in the
normal and abnormal brain (Figure 2). This will require a
system biology approach combined with a clinical and
endo-phenotype approach to understand the function of
the DISC1 interactome (Box 1).
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
DISC1 are candidates for mental illnesses. Additionally,
we can predict and examine genegene interactions. For
example, in a preliminary study, Hennah et al. [50]
reported a genome-wide scan for linkage that was
conditioned on the presence or absence of the DISC1 risk
haplotype, HEP3, from which significant evidence for the
nuclear distribution gene E homolog 1 (NDE1, also known
as NUDE) locus emerged. NDE1 is highly similar to
NDEL1 and also interacts with DISC1. Association
analysis confirmed that NDE1 is a risk factor in
schizophrenia. Therefore, the hope is that the DISC1
interactome will provide multiple entry points through
which to determine the nature and distribution of genetic
risks of major mental illnesses.
Although it would be useful to know more about the
mechanism underlying the normal, schizophrenic or
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Vol.12 No.6 June 2006 259
bipolar brain, and how this is affected by genetic and
environmental variation, for obvious reasons the oppor-
tunities are limited. Useful information comes from post-
mortem studies of brain RNA and protein expression but
there are problems of: (i) uncertain provenance; (ii)
variable and uncertain time to processing; (iii) impact of
prescription and recreational-drug use, and whether this
is known; and (iv) matching of case with control tissue.
Functional brain imaging has already contributed by
giving important information [23], and the resolution is
continuously improving. However, in the foreseeable
future, the resolution will remain at the macro level of
brain region rather than at the level of cell structure. The
selection of subjects and the need for longitudinal testing
are also important factors that are being addressed. An
example is the Edinburgh high-risk study, which is
collecting longitudinal structural and functional brain-
imaging data on affected individuals and their first-degree
relatives [51]. It will be also of interest not only to the
DISC1 risk pathway but also to any confirmed genetic risk
factors to understand whether brain imaging can provide
any new insights into the clinical presentation, course and
response to treatment (Box 1).
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 performance in both
hemizygous and homozygous mutant animals. It will be of
interest to test additional behavioural phenotypes and to
define the exact molecular consequences of the 25bp
deletion on Disc1 isoform expression. Additional natural,
experimentally induced, developmentally regulated and
brain-restricted Disc1 mutants and human DISC1 trans-
genic cell lines would also be valuable. It would be useful
to generate mice that are mutant in specific protein-
interaction domains. On the assumption that these mice
will display behavioural correlates of psychotic and mood
disorders, it would be of great value that new cell- and
tissue-based assays are developed to act as intermediates
between the gene mutation and the behavioural pheno-
type. These might then form the basis for small-molecule
interventions that are aimed at rescuing the mouse
phenotype, before testing in people (Box 1).
Prospects for rational drug development
The DISC1PDE4B 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
260 Review TRENDS in Molecular Medicine
cognitive disorders [55]. Perhaps, for once, mental-health
research will benefit indirectly from well-funded research
programs in other disease domains. Much still needs to be
understood about how, where and when DISC1 and
PDE4B interact to modulate cAMP. Although the task
might be difficult, the development of interaction assays
and ways to modify those interactions with small
molecules would be a worthwhile basic and translational
research objective (Box 1).
Interestingly, although the main focus on NDEL1 has
been to understand its developmental role, this protein
has also a catalytic activity as endo-oligopeptidases [56]
and is thought to be important in processing of neuro-
peptides [57], showing high expression in neuropeptide-
rich brain regions [58,59]. Thus, the potential ramifica-
tions of the DISC1 pathway are extended and the need
and opportunity for testing the DISC1NDE1/NDEL1
complex as an alternative or additional drug target is also
raised (Box 1).
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 in the molecular age of the 21st century away from
the Kraepelian dichotomy that was the mainstay of
clinical practice in the 20th century [60]. Over these
same five years, the understanding of the biological
function of DISC1 has been completely transformed from
the starting point of a novel and unique molecule to our
current appreciation of DISC1 as a protein that interacts
with multiple partners involved in neurodevelopment,
cytoskeletal function and cell signalling. Thus, in the
developing field of biological psychiatry, DISC1 stands out
because there are both genetic and biological evidences
for its role in determining susceptibility to SCZ, schizo-
affective and major depressive disorders [10]. The identifi-
cation of PDE4B as a DISC1 binding partner adds an
important new dimension to the current knowledge of
DISC1 function. There are exciting new possibilities for
disease stratification based upon genetic variation of the
DISC1 interactome, for determining how such variation
predicts clinical course or treatment response and for
rational drug development (Box 1).
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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916

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