Cover Story 2013, Volume 8 Issue 1
Since its discovery over a decade ago, Disrupted in Schizophrenia 1 (DISC1) has been implicated in a wide spectrum of brain-specific phenotypes, ranging from severe mental disorders such as major depression, schizophrenia and bipolar disorder to more subtle alterations of brain structure and function, and including multiple defects of neurodevelopment and neuronal plasticity. Collectively, these observations have established DISC1 as a widely recognised candidate gene for major psychiatric illness, and many studies have exploited it as a tool to dissect the cellular and molecular perturbations underlying these highly heritable disorders. DISC1 encodes a large multifunctional protein that is expressed at relatively high levels in the brain, where it distributes to multiple subcellular compartments in both neurons and glia. DISC1 can physically interact with a large number of other proteins, many of which have well-established functions in several aspects of neuronal development and neurosignalling, and some of which have been independently associated with psychiatric illness. A selected subset of DISC1 binding partners are shown in the central panel of the cover illustration. These include crucial players in i) neuronal progenitor proliferation and neuronal migration, such as DIXDC1, GSK3β, NDE1 and NDEL1, ii) neuronal maturation and integration into functional circuits, such as AKT1, FEZ1 and PDE4, and iii) transcriptional regulation of cognition and circadian functions, such as ATF4. Its widespread subcellular distribution, combined with its high degree of molecular connectivity, led to the conceptualisation of DISC1 as a “scaffold” protein that regulates multiple signalling pathways, most of which are considered of central relevance for psychiatric illness. The earliest piece of evidence linking DISC1 to major psychiatric illness was generated during the course of genetic investigations focused on a large Scottish pedigree (reproduced in the top panel of the cover illustration) presenting a strikingly elevated burden of severe mental disorders, including major depression, schizophrenia and bipolar disorder. In this family, the individuals carrying a balanced t(1;11) translocation that directly interrupts DISC1 coding sequence present a greatly increased risk of developing a severe form of mental illness, while none of the non-carriers have a diagnosis of major mental illness, strongly supporting a causative link between the t(1;11) translocation and major psychiatric illness. This remarkable finding led the way to a large number of independent linkage and association studies, which provided supporting evidence for involvement of DISC1 in some cases of major mental illness outwith the t(1;11) family, and also in some forms autism and neurodegenerative disorders. However, genome-wide approaches have identified no clear association between common variants at this locus and psychiatric illness and, beyond the original translocation event, causative variants await unequivocal identification. Genetic variation in DISC1 has been shown to influence brain structure and/or function in psychiatric patients, their unaffected first-degree relatives, and healthy volunteers with no family history of psychiatric illness, as assessed in neuroimaging and neuropsychological studies. Examples of brain structural abnormalities consistently reported in carriers of common DISC1 missense variants include altered grey matter volume in the hippocampus and prefrontal cortex, focal alterations of cortical thickness in specific brain regions, lateral ventricle enlargement and altered organisation of white matter fibres. These observations are particularly relevant because they reflect structural alterations that are commonly observed in the brains of psychiatric patients and, albeit to a lesser extent, their first-degree relatives, and that are consequently thought to be components of the genetically determined biological perturbations that contribute to an individual’s susceptibility to mental illness. Other studies that focused on functional and cognitive parameters, such as the activation of specific brain areas during cognitive tasks, the evaluation of the subjects’ performance in various neurocognitive tests, or the measurement of the brain’s electrical activity, also found significant effects of DISC1 variants. Similarly to the structural alterations mentioned above, these functional and cognitive effects can be related to the typical deficits identified in psychiatric patients. Collectively, these findings originated the hypothesis that DISC1 may influence genetic risk of psychiatric illness by impacting on several aspects of neurodevelopment and neuronal circuit formation. The proposed role of DISC1 as an important regulator of neurodevelopment, neuronal connectivity and behaviour is corroborated by a large number of in vitro and in vivo studies based on genetic manipulations of DISC1 expression. As predicted from the earlier investigations of the DISC1 protein interactome, which highlighted a large number of partners involved in neurodevelopment and neuronal plasticity, these studies demonstrated that DISC1 plays key roles in neuronal progenitor proliferation, neuronal migration, neuronal maturation, and integration into existing functional networks, as well as in neurotransmission. Thus, DISC1 may influence three interconnected domains of brain biology: i) mood, behaviour and psychiatric illness, ii) brain architecture and cognition, and iii) cellular and molecular events that govern brain development. The diverse genetic and biological evidence supporting an influence of DISC1 upon susceptibility to a range of brain disorders, spanning from major psychiatric illness to autism and neurodegeneration, is detailed and discussed in this issue in a review by Thomson and colleagues. In this review, the authors additionally discuss how a better understanding of the DISC1 interactome and its perturbations by DISC1 mutations may propel the discovery of innovative treatments by aiding the identification of biological pathways that could be relevant to the treatment of psychiatric illness.[Detail] ...
