DISC1
Disrupted in schizophrenia 1 is a protein that in humans is encoded by the DISC1 gene. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, clinical depression, bipolar disorder, and other psychiatric conditions. The cellular functions that are disrupted by permutations in DISC1, which lead to the development of these disorders, have yet to be clearly defined and are the subject of current ongoing research. Although recent genetic studies of large schizophrenia cohorts have failed to implicate DISC1 as a risk gene at the gene level, the DISC1 interactome gene set was associated with schizophrenia, showing evidence from genome-wide association studies of the role of DISC1 and interacting partners in schizophrenia susceptibility.
Discovery
In 1970, researchers from the University of Edinburgh performing cytogenetic research on a group of juvenile offenders in Scotland found an abnormal translocation in chromosome 1 of one of the boys, who also displayed characteristics of an affective psychological disorder. After this initial observation, the boy's family was studied and it was found that 34 out of 77 family members displayed the same translocation. According to the Diagnostic and Statistical Manual of Mental Disorders criteria, sixteen of the 34 individuals identified as having the genetic mutation were diagnosed with psychiatric problems. In contrast, five of the 43 unaffected family members were identified to have psychological indispositions. The psychiatric illnesses observed in the family ranged from schizophrenia and major depression to bipolar disorder and adolescent conduct disorder. After studying this large Scottish family for four generations, in 2000, this gene was given the name "DISC1". The name was derived from the basis of the molecular nature of the mutation: the translocation directly disrupts the gene.Importance of genetic studies
The implication of genetics in psychiatric illnesses is not unique to schizophrenia, though the heritability of schizophrenia has been calculated as high as 80%. The continued research of the family following the discovery of the translocation yielded statistical analysis of the probability of observing the simultaneous occurrence, or co-inheritance, of psychological conditions and the translocation. This concept was measured quantitatively using the LOD, or logarithm of the odds value. The higher the LOD value, the stronger the correlation between the presence of the translocation and given disease is thought to be. The LOD for the chromosome 1 translocation and identification of schizophrenia alone in the Scottish family was found to be 3.6. The LOD value of the translocation and a broader number of diagnoses was found to be 7.1.Besides large familial-based studies in which the pedigrees of various family members are examined, twin studies have also been a source of support for researchers in the investigation of DISC1. In a meta-analysis of twin studies, twelve out of fourteen were found to support the fact that from a genetic perspective, schizophrenia is a complex trait that depends on both genetic and environmental factors. Such findings have encouraged researchers to continue with both macro-analysis of the disorders affecting individuals with the mutation, as well as explore the micro-level.
Gene location and transcription
The DISC1 gene is situated at chromosome 1q42.1 and overlaps with DISC2 open reading frame. Multiple DISC1 isoforms have been identified at the RNA level, including a TSNAX-DISC1 transgene splice variant, and at the protein level. Of the isolated RNA isomers, 4 have been confirmed to be translated namely Long form, Long variant isoform, Small isoform, and Especially small isoform. Human DISC1 is transcribed as two major splice variants, L form and Lv isoform. The L and Lv transcripts utilize distal and proximal splice sites, respectively, within exon 11. The L and Lv protein isoforms differ by only 22 amino acids within the C-terminus.Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
DISC1 homologues have been identified in all major vertebrate families including the common chimpanzee, the rhesus monkey, the house mouse, the brown rat, zebrafish, pufferfish, cattle, and dogs; additionally homologues have been described for invertebrate and plant phyla.
Protein structure and subcellular distribution
The protein encoded by this gene is predicted to contain a coiled coil motif rich C-terminal domain, and a N-terminal globular domain. The N-terminus contains two putative nuclear localization signals, and a serine-phenylalanine-rich motif of unknown significance. The C-terminus contains multiple regions with coiled-coil forming potential, and two leucine zippers that may mediate protein-protein interactions.The protein locates to the nucleus, centrosome, cytoplasm, mitochondria, axons and synapses. Mitochondria are the predominant site of endogenous DISC1 expression, with at least two isoforms occupying internal mitochondrial locations. No known functional homologues exist for this protein in humans, although it does have broad homology to scaffold proteins. The DISC1 protein function appears to be highly diverse and its functional role in cellular processes is dependent upon the cellular domain it is located in. The presence or absence of certain protein interaction domains or targeting motifs may confer specific functions and influence sub cellular targeting, therefore it is probable that alternative splicing codetermines both the function and the intracellular location of DISC1.
Function
Many studies have provided insight into the normal function of the DISC1 protein, though much remains to be clearly defined. DISC1 is functionally involved in several processes that regulate neural development and brain maturation such as neuronal proliferation, differentiation, migration, cAMP signaling, cytoskeletal modulation, and translational regulation via various signaling pathways. Much of what is understood about the normal function of DISC1 has been uncovered through studies on zebrafish and mice as model organisms. In zebrafish, DISC1 is essential for forebrain development and GSK3/β-catenin signaling, while in mice the DISC1-GSK3 pathway regulates proliferation of neural progenitor cells in the cortex and adult dentate gyrus. This data suggests a direct DISC1 GSK3/β-catenin interaction.DISC1 functions through a rich protein-protein interaction network, named the "DISC1 interactome" by researchers. Among its known interaction partners are 14-3-3ε, LIS1 and the PDE4B enzyme. DISC1 may play an important role in neuroplasticity via interactions with molecules of the cytoskeleton and centrosome, such as NUDEL and LIS1. The protein also enables the activity of dynein, a microtubule protein. Controlling transport of microtubules is involved in neuronal migration, neurite outgrowth, and axon formation.
DISC1 is highly expressed during critical periods of brain development, particularly in the embryonic ventricular and subventricular zones of the cortex, where neural progenitor cells are found. This localization suggests that DISC1 is an important regulator of embryonic and adult neurogenesis, and may regulate proliferation and/or differentiation. Levels of the protein in cycling neural progenitor cells affects whether they differentiate into neurons or remain as progenitors. Expression profile is highest in the hippocampus during development and remains highly expressed in the adult dentate gyrus and olfactory bulb, regions where adult neurogenesis is present. DISC1 has also been shown to regulate tempo of neuronal integration into the brain and guidance of positioning of new neurons.
Due to localization of the protein found at the synapse, DISC1 is also likely to play a key role in postsynaptic density, however this novel role is not yet fully understood.