DISC1
Encyclopedia
Disrupted in schizophrenia 1 is a protein
that is encoded by the DISC1 gene
in humans. 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.
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 (Fourth Edition) (or DSM-IV
) 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
(which the original research subject had). 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.
, or logarithm of the odds value. The higher the LOD value, the stronger the correlation between the presence of the translocation and given disease(s) 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 (including schizophrenia, schizoaffective disorder, bipolar affective disorder, and recurrent major depression) 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 afflicting individuals with the mutation, as well as explore the micro-level.
. 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 (L), Long variant isoform (Lv), Small isoform (S), and Especially small isoform (Es). 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 homologue's have been described for invertebrate and plant phyla ,.
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 zipper
s that may mediate protein-protein interaction
s.
The protein locates to the nucleus
, centrosome
, cytoplasm
, mitochondria, axon
s and synapse
s. 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.
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 organism
s. 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 cell
s 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 microtubule
s 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 zone
s 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.
. In postmortem brain samples of Schizophrenia patients there is an increase in insoluble DISC1 oligomer aggregates, indicative of a common link with other neurological disorders characterised by protein agregation, namely Alzheimer's Disease
, Parkinson's Disease
, and Huntington's Disease
.
and ATF5
are members of the leucine zipper
activating transcription factor
/ CREB
family. They are known to bind to and regulate the function of GABAB receptors in synapses and are involved in signal transduction
from the cell membrane to the nucleus. Both proteins interact with DISC1 and GABAB receptors via their second C-terminal leucine zipper domain, therefore DISC1 is able to regulate GABAB receptor function through its interaction with ATF4/ATF5.
and elongation protein ζ-1 (FEZ1
). FEZ1 is a mammalian homolog of the C. elegans
UNC-76 protein involved in axonal outgrowth and fasciculation. The C-terminal region of FEZ1 (aa 247-392) is required for interaction with DISC1. A DISC1 region (aa 446-633), containing two stretches with coiled-coil-forming potential is critical for its interaction with FEZ1. DISC1-FEZ1 interaction is enhanced during neuro-differentiation, and expression of the FEZ1-binding domain of DISC1 has a dominant negative effect on neurite outgrowth, which implies co-operation of DISC1 and FEZ1 in this process.
. Activation of rac1 by kal-7 leads to increased spine size and synaptic strength through regulation of the actin
cytoskeleton by rac1. DISC1 is able to bind to kal-7, confining its access to rac1, and in turn regulate spinal formation. Activation of NMDA receptor
s causes dissociation of DISC1 and kal-7, leaving kal-7 available to activate rac1.
that controls the polymerization and stabilization of microtubule networks in neurons, and thereby influence cell shape and intracellular transport of vesicles
and organelle
s. MAP1A binds to the far N-terminus (aa 293-696) of DISC1, and the amino terminus of DISC1 binds to the LC2 subunit of MAP1A. The LC2 subunit of MAP1A contains an actin-binding domain and is necessary and sufficient for microtubule binding and polymerization
, therefore DISC1 is able to regulate the ability of MAP1A to polymerize and stabilize microtubules and traffic proteins to their correct localization in the synaptic architecture.
, also called NUDEL), where it is part of a protein complex involved in cytoskeletal processes of neuronal migration, including nucleokinesis and neurite outgrowth. NUDEL is also known to play a role in axon regeneration and has an additional DISC1-modulated function as a cysteine endopeptidase
. Localization of NUDEL to axons is dependent on expression of DISC1. NUDEL binds to a 100 amino acid domain of DISC1 (aa 598-697) containing a coiled coil domain and a leucine zipper. The amino acid domain of NUDEL that binds DISC1 is the carboxyl terminal 100 amino acids of the protein (aa 241-345), which contains a cytoplasmic dynein
binding site.
Other interactions include: ACTN2
, CEP63
, EIF3A
, RANBP9
, and SPTBN4
.
, diminution of gray matter volume in hippocampal and prefrontal regions. These abnormalities are also seen as symptoms of schizophrenia. As DISC1 function is involved in neurogenesis and neuroplasticity, vulnerability to schizophrenia may involve dysfunction in the hippocampus, a brain region in which adult neurogenesis occurs.
of 97 Finnish families affected by autism
and Asperger’s syndrome
revealed repeated DNA sequences within the DISC1 gene in those diagnosed with autism. Furthermore, a single nucleotide change in the gene was found to be present in 83% of family members with Asperger’s syndrome. A recent family study has reported a large chromosome 1 deletion that includes loss of DISC1 in a young boy diagnosed with autism. A link between DISC1 duplication and autism has also been suggested by the finding of a seven-gene duplication that includes DISC1 carried by two brothers with autism and mild retardation. These alterations in people with the disorder are rare, however, as none were found in a screening of 260 Belgians with autism.
Transgenic model organism strains generated with mutated or absent DISC1 suggest that the gene may contribute to at least some autistic abnormalities. Mice with lowered levels of DISC1 expression exhibit abnormal response to electrical stimulation, a decrease of dopamine synthesis, and an inability to filter unnecessary sensory information. Studies of expression of mutant DISC1 prenatally and postnatally have demonstrated varying effects, indicating the possibility that early postnatal expression of mutant DISC1 causes features of autism. Many more studies are necessary to confirm these suggestions.
In addition to DISC1, the antisense partner has been identified as DISC2, a noncoding RNA gene that may be involved in regulating the gene locus. However, structure and function of DISC2 remain unknown and may provide insight into how DISC1 is regulated.
Rare mutations in DISC1 other than the original translocation have been discovered and require further investigation. Furthermore, posttranslational processing and its effect on isoform expression, which also contributes to protein function and may be involved in some forms of disease, remains to be studied. The ability to predict the impact of different types of mutations on protein function and resulting psychiatric phenotype is crucial for the development of targeted treatments.
Family studies continue to provide an important approach towards deepening understanding of the biological nature of the gene and its clinical implications. While the original Scottish family in which DISC1 was discovered is still being considered, other familial populations in different countries have also become the focus of research in the past decade. In 2005, an American family was found to also possess a frameshift mutation in the DISC1 gene, which again co-segregated with schizophrenia and schizoaffective disorder. Characterized by a deletion of four base-pairs, the mutation was found in two siblings, one with schizophrenia and the other with schizoaffective disorder. Similar studies have also been done with Taiwanese and Finnish families.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that is encoded by the DISC1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in humans. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, neuronal axon and dendrite outgrowth, mitochondrial transport, fission
Mitochondrial fission
Mitochondria can divide by fission and since they require mitochondrial DNA for their function, fission is coordinated with DNA replication. Some of the proteins that are involved in mitochondrial fission have been identified and some of them are associated with mitochondrial...
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
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, 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.
Discovery
In 1970, researchers performing cytogeneticCytogenetics
Cytogenetics is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-Banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ...
research on a group of juvenile offenders in Scotland found an abnormal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
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 (Fourth Edition) (or DSM-IV
Diagnostic and Statistical Manual of Mental Disorders
The Diagnostic and Statistical Manual of Mental Disorders is published by the American Psychiatric Association and provides a common language and standard criteria for the classification 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
Conduct disorder
Conduct disorder is psychological disorder diagnosed in childhood that presents itself through a repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate norms are violated...
(which the original research subject had). 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 afflictions and the translocation. This concept was measured quantitatively using the LODGenetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
, or logarithm of the odds value. The higher the LOD value, the stronger the correlation between the presence of the translocation and given disease(s) 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 (including schizophrenia, schizoaffective disorder, bipolar affective disorder, and recurrent major depression) 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 afflicting 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 frameOpen reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
. Multiple DISC1 isoforms have been identified at the RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
level, including a TSNAX
TSNAX
Translin-associated protein X is a protein that in humans is encoded by the TSNAX gene.-Further reading:...
-DISC1 transgene splice variant, and at the protein level. Of the isolated RNA isomers, 4 have been confirmed to be translated namely Long form (L), Long variant isoform (Lv), Small isoform (S), and Especially small isoform (Es). 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
Danio rerio
The zebrafish, Danio rerio, is a tropical freshwater fish belonging to the minnow family of order Cypriniformes. It is a popular aquarium fish, frequently sold under the trade name zebra danio, and is an important vertebrate model organism in scientific research.-Taxonomy:The zebrafish are...
, pufferfish
Takifugu rubripes
Takifugu rubripes is a pufferfish in the genus Takifugu. A feature of this species is that it has a very small genome, which is used as a ‘reference’ for identifying genes and other elements in human and other vertebrate genomes...
, cattle, and dogs; additionally homologue's 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 coilCoiled coil
A coiled coil is a structural motif in proteins, in which 2-7 alpha-helices are coiled together like the strands of a rope . Many coiled coil type proteins are involved in important biological functions such as the regulation of gene expression e.g. transcription factors...
motif
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
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 zipper
Leucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...
s that may mediate protein-protein interaction
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
s.
The protein locates to the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, centrosome
Centrosome
In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883...
, cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, mitochondria, axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s and synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s. Mitochondria are the predominant site of endogenous DISC1 expression, with at least two isoforms occupying internal mitochondrial locations. No known functional homologues
Homology (chemistry)
In chemistry, homology refers to the appearance of homologues. A homologue is a compound belonging to a series of compounds differing from each other by a repeating unit, such as a methylene group, a peptide residue, etcetera....
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
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA 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 developmentNeural development
Neural development comprises the processes that generate, shape, and reshape the nervous system, from the earliest stages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to address the underlying mechanisms...
and brain maturation such as neuronal proliferation, differentiation, migration, cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
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 organism
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
s. In zebrafish, DISC1 is essential for forebrain development and GSK3
GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates...
/β-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
signaling, while in mice the DISC1-GSK3 pathway regulates proliferation of neural progenitor cell
Progenitor cell
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
s in the cortex and adult dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
. 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
PAFAH1B1
Platelet-activating factor acetylhydrolase IB subunit alpha is an enzyme that in humans is encoded by the PAFAH1B1 gene.According to one study, PAFAH1B1 interacts with VLDLR receptor activated by reelin.-Genomics:...
and the PDE4B
PDE4B
cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.This gene is a member of the type IV, cyclic AMP -specific, cyclic nucleotide phosphodiesterase family...
enzyme. DISC1 may play an important role in neuroplasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
via interactions with molecules of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
and centrosome, such as NUDEL
NDEL1
Nuclear distribution protein nudE-like 1 is a protein that in humans is encoded by the NDEL1 gene.This gene encodes a thiol-activated oligopeptidase that is phosphorylated in M phase of the cell cycle...
and LIS1. The protein also enables the activity of dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
, a microtubule protein. Controlling transport of microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s 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 zone
Subventricular zone
The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....
s 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
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
during development and remains highly expressed in the adult dentate gyrus and olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
, 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
Postsynaptic density
The postsynaptic density is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron...
, however this novel role is not yet fully understood.
Protein interactions
The DISC1 protein has no known enzymatic activity; rather it exerts its effect on multiple proteins through interactions to modulate their functional states and biological activities in time and space. These include:DISC1
DISC1 has been shown to self-associate, to form dimers, multimers, and oligomers. The ability of DISC1 to form complexes with itself may be important in regulating its affinity for interacting partners such as NDEL1NDEL1
Nuclear distribution protein nudE-like 1 is a protein that in humans is encoded by the NDEL1 gene.This gene encodes a thiol-activated oligopeptidase that is phosphorylated in M phase of the cell cycle...
. In postmortem brain samples of Schizophrenia patients there is an increase in insoluble DISC1 oligomer aggregates, indicative of a common link with other neurological disorders characterised by protein agregation, namely Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, Parkinson's Disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, and Huntington's Disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
.
ATF4/ATF5
ATF4ATF4
Activating transcription factor 4 , also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.- Function :...
and ATF5
ATF5
Activating transcription factor 5, also known as ATF5, is a protein that, in humans, is encoded by the ATF5 gene.- Function :First described by Nishizawa and Nagata, ATF5 has been classified as a member of the activating transcription factor /cAMP response-element binding protein family.ATF5...
are members of the leucine zipper
Leucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...
activating transcription factor
Activating transcription factor
In molecular biology, activating transcription factor, ATF, is a class of AP-1 transcription factor dimers.Genes include ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7....
/ CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
family. They are known to bind to and regulate the function of GABAB receptors in synapses and are involved in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
from the cell membrane to the nucleus. Both proteins interact with DISC1 and GABAB receptors via their second C-terminal leucine zipper domain, therefore DISC1 is able to regulate GABAB receptor function through its interaction with ATF4/ATF5.
FEZ1
DISC1 participates in neurite outgrowth through its interaction with the fasciculationFasciculation
A fasciculation , or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers...
and elongation protein ζ-1 (FEZ1
FEZ1
Fasciculation and elongation protein zeta-1 is a protein that in humans is encoded by the FEZ1 gene.This protein is present in neurons, and it is believed to block the process of infection of these cells by HIV.-Interactions:...
). FEZ1 is a mammalian homolog of the C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
UNC-76 protein involved in axonal outgrowth and fasciculation. The C-terminal region of FEZ1 (aa 247-392) is required for interaction with DISC1. A DISC1 region (aa 446-633), containing two stretches with coiled-coil-forming potential is critical for its interaction with FEZ1. DISC1-FEZ1 interaction is enhanced during neuro-differentiation, and expression of the FEZ1-binding domain of DISC1 has a dominant negative effect on neurite outgrowth, which implies co-operation of DISC1 and FEZ1 in this process.
Kalirin-7
The DISC1 protein plays a role in the process of regulating spine form and function through its interactions with kalirin-7 (kal-7). Kal-7 is a regulator of spine morphology and synaptic plasticity in association with neuronal activity. Kal-7-dependent regulation of spine formation occurs through its activity as a GDP/GTP exchange factor for Rac1RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
. Activation of rac1 by kal-7 leads to increased spine size and synaptic strength through regulation of the actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
cytoskeleton by rac1. DISC1 is able to bind to kal-7, confining its access to rac1, and in turn regulate spinal formation. Activation of NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s causes dissociation of DISC1 and kal-7, leaving kal-7 available to activate rac1.
MAP1A
DISC1 shows strong interaction with the microtubule-associated protein MAP1AMAP1A
Microtubule-associated protein 1A is a protein that in humans is encoded by the MAP1A gene.-Further reading:...
that controls the polymerization and stabilization of microtubule networks in neurons, and thereby influence cell shape and intracellular transport of vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
and organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s. MAP1A binds to the far N-terminus (aa 293-696) of DISC1, and the amino terminus of DISC1 binds to the LC2 subunit of MAP1A. The LC2 subunit of MAP1A contains an actin-binding domain and is necessary and sufficient for microtubule binding and polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
, therefore DISC1 is able to regulate the ability of MAP1A to polymerize and stabilize microtubules and traffic proteins to their correct localization in the synaptic architecture.
NDEL1/NUDEL
DISC1 is localized to the centrosome, the primary microtubule organizing center of the cell, via interaction with nuclear distribution gene homologue-like 1 (NDEL1NDEL1
Nuclear distribution protein nudE-like 1 is a protein that in humans is encoded by the NDEL1 gene.This gene encodes a thiol-activated oligopeptidase that is phosphorylated in M phase of the cell cycle...
, also called NUDEL), where it is part of a protein complex involved in cytoskeletal processes of neuronal migration, including nucleokinesis and neurite outgrowth. NUDEL is also known to play a role in axon regeneration and has an additional DISC1-modulated function as a cysteine endopeptidase
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
. Localization of NUDEL to axons is dependent on expression of DISC1. NUDEL binds to a 100 amino acid domain of DISC1 (aa 598-697) containing a coiled coil domain and a leucine zipper. The amino acid domain of NUDEL that binds DISC1 is the carboxyl terminal 100 amino acids of the protein (aa 241-345), which contains a cytoplasmic dynein
Dynein
Dynein is a motor protein in cells which converts the chemical energy contained in ATP into the mechanical energy of movement. Dynein transports various cellular cargo by "walking" along cytoskeletal microtubules towards the minus-end of the microtubule, which is usually oriented towards the cell...
binding site.
Other interactions include: ACTN2
Actinin, alpha 2
Actinin, alpha 2, also known as ACTN2, is a protein which in humans is encoded by the ACTN2 gene.- Function :Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an...
, CEP63
CEP63
Centrosomal protein of 63 kDa is a protein that in humans is encoded by the CEP63 gene.-Further reading:...
, EIF3A
EIF3A
Eukaryotic translation initiation factor 3 subunit A is a protein that in humans is encoded by the EIF3A gene.-Interactions:EIF3A has been shown to interact with EIF3EIP, EIF4B, DISC1, FBXO32, EIF3D, EIF3C, EIF4G2, EIF3B, EIF3J, EIF3S6, EIF3F, EIF3G, EIF3H, EIF3I and EIF3K.-Further reading:...
, RANBP9
RANBP9
Ran-binding protein 9 is a protein that in humans is encoded by the RANBP9 gene.-Interactions:RANBP9 has been shown to interact with C-Met, DYRK1B, USP11, DISC1, Androgen receptor, Glucocorticoid receptor, S100A7, HIPK2 and MKLN1.-Further reading:...
, and SPTBN4
SPTBN4
Spectrin, beta, non-erythrocytic 4, also known as SPTBN4, is a protein which in humans is encoded by the SPTBN4 gene.Spectrin is an actin crosslinking and molecular scaffold protein that links the cell membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement...
.
Clinical implications
Aberrations of DISC1 are considered a generalized risk factor in major psychiatric diseases and have also been implicated in memory deficits and abnormal patterns of brain activity. DISC1 translocation increases the risk of developing schizophrenia, bipolar disorder, or major depression by about 50-fold in comparison to the general population. Efforts to model DISC1 disease biology in transgenic mice, Drosophila, and zebrafish have provided psychiatric disease implications related to DISC1 mutations. However, no specific variant is consistently associated with development of mental disorders, indicating allelic heterogeneity in psychiatric disease. The impact of variants in the DISC1 gene on expression and protein function is not yet clearly defined and associated variants are not necessarily causative.Schizophrenia
Schizophrenia affects 1% of the general population and is highly heritable, providing an indication of a genetic basis. DISC1 has been associated with neurological abnormalities such as delusions, deficits in long term and working memoryWorking memory
Working memory has been defined as the system which actively holds information in the mind to do verbal and nonverbal tasks such as reasoning and comprehension, and to make it available for further information processing...
, diminution of gray matter volume in hippocampal and prefrontal regions. These abnormalities are also seen as symptoms of schizophrenia. As DISC1 function is involved in neurogenesis and neuroplasticity, vulnerability to schizophrenia may involve dysfunction in the hippocampus, a brain region in which adult neurogenesis occurs.
Autism and Asperger’s syndrome
In 2008, a genetic screenGenetic screen
A genetic screen is a procedure or test to identify and select individuals who possess a phenotype of interest. A genetic screen for new genes is often referred to as forward genetics as opposed to reverse genetics, the term for identifying mutant alleles in genes that are already known...
of 97 Finnish families affected by autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
and Asperger’s syndrome
Asperger syndrome
Asperger's syndrome that is characterized by significant difficulties in social interaction, alongside restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development...
revealed repeated DNA sequences within the DISC1 gene in those diagnosed with autism. Furthermore, a single nucleotide change in the gene was found to be present in 83% of family members with Asperger’s syndrome. A recent family study has reported a large chromosome 1 deletion that includes loss of DISC1 in a young boy diagnosed with autism. A link between DISC1 duplication and autism has also been suggested by the finding of a seven-gene duplication that includes DISC1 carried by two brothers with autism and mild retardation. These alterations in people with the disorder are rare, however, as none were found in a screening of 260 Belgians with autism.
Transgenic model organism strains generated with mutated or absent DISC1 suggest that the gene may contribute to at least some autistic abnormalities. Mice with lowered levels of DISC1 expression exhibit abnormal response to electrical stimulation, a decrease of dopamine synthesis, and an inability to filter unnecessary sensory information. Studies of expression of mutant DISC1 prenatally and postnatally have demonstrated varying effects, indicating the possibility that early postnatal expression of mutant DISC1 causes features of autism. Many more studies are necessary to confirm these suggestions.
Bipolar disorder
Linkage studies in extended families multiply affected with bipolar disorder also provide evidence for DISC1 as a genetic factor in the etiology of bipolar disorder. In 1998, a follow-up study was conducted of the large Scottish family in which DISC1 was first discovered. Additional family members with the original translocation who developed major psychotic illness, including bipolar disorder, were identified.Research directions
As DISC1 investigation continues to be an emerging area of study, many unanswered questions regarding the biological function of the protein and its implications in psychiatric disorders remain. In depth understanding of DISC1 as a genetic risk factor for psychiatric disorders provides a possible target for developing new drug therapies and preventative measures. The pathways regulated by DISC1 interaction may provide possible avenues for therapeutic opportunities to reverse related deficits. Definitive genetic architecture, risk distribution, and their correlation with prognosis is crucial to determining response to new drug treatments.In addition to DISC1, the antisense partner has been identified as DISC2, a noncoding RNA gene that may be involved in regulating the gene locus. However, structure and function of DISC2 remain unknown and may provide insight into how DISC1 is regulated.
Rare mutations in DISC1 other than the original translocation have been discovered and require further investigation. Furthermore, posttranslational processing and its effect on isoform expression, which also contributes to protein function and may be involved in some forms of disease, remains to be studied. The ability to predict the impact of different types of mutations on protein function and resulting psychiatric phenotype is crucial for the development of targeted treatments.
Family studies continue to provide an important approach towards deepening understanding of the biological nature of the gene and its clinical implications. While the original Scottish family in which DISC1 was discovered is still being considered, other familial populations in different countries have also become the focus of research in the past decade. In 2005, an American family was found to also possess a frameshift mutation in the DISC1 gene, which again co-segregated with schizophrenia and schizoaffective disorder. Characterized by a deletion of four base-pairs, the mutation was found in two siblings, one with schizophrenia and the other with schizoaffective disorder. Similar studies have also been done with Taiwanese and Finnish families.