Advances In Medical Sciences Assignment Biology Essay

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Dysbindin-1 is set apart from other paralogs of the dysbindin family by a coiled coil domain vital in interactions with other proteins. Dysbindin-1 is the only gene associated with schizophrenia thus far. Its gene, DTNBP1, has three major transcripts, dysbidin-1A, 1B, and 1C encoding isoforms running on western blots at about 50, 37, and 33 kDa respectively.

Variation in the gene encoding dysbindin-1, dystrobrevin-binding protein 1 has often been associated with schizophrenia. Several studies have also found that dysbindin-1 gene and protein expression are altered in two affected brain areas in that disorder such as the dorsolateral prefrontal cortex and the hippocampal formation.

Schizophrenia is a severe, chronic disorder, in which individuals experience hallucinations, delusions, disorganized thinking, and a decline in social functioning. Although the cause of Schizophrenia is unknown, at present, it is hypothesized to be a neuro-developmental disorder, as well as a disease of abnormal synaptic connectivity.

Schizophrenia possibly results from a combination of environmental factors and genetic susceptibility.1 Changes in biochemical markers for multiple neurotransmitter systems have been implicated in schizophrenia, thus linking genetic and environmental risk factors with altered neurotransmission.

While the link between genetic variation in DTNBP1 and schizophrenia has been questioned lately, there is growing evidence that the associations found reflect actual susceptibility variants in the gene. Even in the absence of such variants, altered dysbindin-1 gene and protein expression have been found in the dorsolateral prefrontal cortex and hippocampal formation of schizophrenia cases.

These changes may contribute to the pathophysiology of the disorder by altering brain development, dopaminergic and glutamatergic transmission, functional connectivity of neuronal populations in the cerebral cortical and the hippocampal formation, and cognition.

Gene Expression:

Gene expression of dysbindin-1 is everywhere in the body, including the brain and is often higher in number in cancerous tissue. In the developing brain, there is peak expression during neurogenesis and during adolescence. In the adult brain, the highest gene expression found to date is in the temporal neocortex, hippocampal formation, and dopamine-rich areas of the brain, specifically the substantia nigra-ventral tegmental area and the areas it supplies such as the dorsolateral prefrontal cortex, nucleus accumbens, and putamen.

The family has three paralogs dysbindin-1, 2, and 3. They are each encoded by a different gene and expressed in more than one isoform. There are at least eight family members in humans. Dysbindin-1A, 1B, 1C, 2A, 2B, 2C, 3A, and 3B are examples. Dysbindin-1 is distinguished from other paralogs of the dysbindin family by the presence of a coiled coil domain vital for interactions with other proteins.

While present in neuronal cell bodies throughout the central nervous system, dysbindin-1 is significantly enriched only in certain synaptic fields, mainly those known to be dopaminergic, glutamatergic, and/or GABAergic.

In synaptic tissue of the human brain, dysbindin-1A is mainly concentrated in postsynaptic density fractions, dysbindin-1B in synaptic vesicle fractions, and dysbindin-1C in both those fractions.

It is unknown as of yet if the isoforms differ in binding partners. They are however, collectively known to bind a large number of proteins, including several proteins belonging to the biogenesis of lysosome-related organelles complex 1 (BLOC-1).

While schizophrenia-associated SNPs in DTNBP1 have not been proven to affect transcription of the gene, it has been reported that altered DTNBP1 gene expression does occur in schizophrenia, specifically in immortalized lymphocytes, the dorsolateral prefrontal cortex (DLPFC), and the hippocampal formation.15

Protein Product

Protein expression of dysbindin-1 is also everywhere in the body and is detectable in cell bodies of virtually all neuronal populations. Levels of somatal protein are variable, however, with the highest levels found in areas listed above where gene expression is highest.

High levels of dysbindin-1 protein expression are also seen in certain synaptic fields. Where these have been examined with immunoEM, dysbindin-1 has been found mainly along microtubules of dendrites and axons, in postsynaptic densities (PSDs) of dendritic spines, and around synaptic vesicles.

Tissue fractionation of whole brain tissue reveals that dysbindin-1A is most highly concentrated in PSD fractions, dysbindin -1B in synaptic vesicle fractions, and dysbindin-1C in both PSD and synaptic vesicle fractions.

Dysbindin-1 has a large number of binding partners, which collectively comprises the dysbindin-1 interactome. Nearly half are members of BLOC-1 (muted, pallidin, and snapin). Another, mysospryn, binds a protein (desmin) that interacts with BLOC-1 in muscle.2 Two other members of the interactome, a- and b-dystrobrevin, are part of the dystrophin glycoprotein complex but it has been questioned whether or not these are physiological binding partners of dysbindin-1.

Dysbindin family proteins lack motifs suggestive of direct binding to actin, DNA, RNA, or ribosomes. They also lack motifs indicative of sorting to, or retention in, the endoplasmic reticulum (ER), Golgi apparatus, mitochondria, or peroxisomes.

Efforts to localize and quantify dysbindin-1 protein in tissue have been hampered by problems in generating antibodies which are specific for the protein. Like most other BLOC-1 proteins, it is only weakly immunogenic.

Candidate antibodies are often partially or wholly non-specific. Therefore it is of upmost importance that they are validated with carefully chosen positive and negative controls.

The best positive control is purified, full-length protein. The ideal negative control for antibodies raised against mouse isoforms would be tissue from DTNBP-1 knockout mice. Since such mice are not currently available, the best alternative is tissue derived from homozygous sandy mice, which lack detectable dysbindin-1 due to a DTNBP-1 mutation.

Predicted phosphorylation sites in dysbindin family proteins. The types of kinases likely to phosphorylate a given site (if known) are indicated by coded flags attached to the vertical markers at that site.

Gene Manipulation/ Animal Models

The ~37 kDa isoform cannot be studied in mice, which appear to lack an ortholog of human dysbindin-1B.

An animal model of dysbindin-1's functions is available in the sandy (sdy) mouse, which has a naturally occurring deletion mutation in DTNBP1 that leads to loss of dysbindin-1 in homozygous mice, which also shows a loss or reduction in other BLOC-1 binding partners.

Among the many abnormalities of homozygous sdy mice are increased dopamine transmission in limbic tissue, decreased glutamate release and NMDA-mediated postsynaptic currents in prefrontal cortex, smaller excitatory evoked responses and loss of inhibitory responses after stimulation in the hippocampal formation, and severe deficits in spatial learning and memory processes.

The homozygous sdy mouse shares behavioral and biological features of schizophrenia, it is currently unclear if it serves an animal model of that disorder. It may, however, model cognitive aspects of schizophrenia.

As it implies, the sdy mouse is not only a model of dysbindin-1 functions, but also of BLOC-1 functions. It should be recognized, however, that it is not a perfect model of the latter, because dysbindin-1 binds more than just BLOC-1 proteins.

Among the many abnormalities of homozygous sdy mice are increased dopamine transmission in the tissues of their limbs, decreased glutamate release and NMDA-mediated postsynaptic currents in prefrontal cortex, smaller excitatory evoked responses and loss of inhibitory responses after stimulation in the hippocampal formation, and severe deficits in spatial learning and memory processes.

While the homozygous sdy mouse shares behavioural and biological features of schizophrenia, it is currently uncertain if it serves an animal model of that disorder. It may, however, model cognitive aspects of schizophrenia. It should be recognized, however, that it is not a perfect model of the latter, because dysbindin-1 binds more than just BLOC-1 proteins.

Gene Structure

Dysbindin-1 consists of an amino terminal region (NTR) of variable length, a coiled coil domain (CCD) not found in other dysbindin paralogs, and a relatively length carboxyterminal region (CTR). This region consists of the dysbindin domain (DD), two uncharacterized CTR segments (X1 and X2), and in some isoforms a terminal PEST domain, which promotes rapid degradation via conformational changes induced by factors such as phosphorylation state.3

In humans, the gene covers 140.26 kb on the petite (p) arm of chromosome 6 at cytogenic band 22.3 such as 6p22.3. Its gene, DTNBP1, has three major transcripts encoding isoforms running on western blots at approximately 50, 37, and 33 kDa, dysbindin-1A, -1B, and -1C, respectively.

Transcription of the human DTNBP1 gene can generate at least 16 different mRNAs. Their complete exon coding sequences are identified and are predicted to contain both a coiled coil domain and a dysbindin domain.

They would encode proteins 338, 334, 219, 212, and 208 aa in length, designated here as dysbindin-1D, -1E, -1F, -1G, and -1H, respectively. These isoforms may be expressed only in certain cell types under certain developmental or physiological conditions.

For example, b has been detected only in neuroblastomas, c only in dorsolateral prefrontal cortex, lymphomas, the placenta, T cell leukaemia, and uterine sarcomas, and f only in small cell lung carcinomas.

There are at least three isoforms of dysbindin-1 in primates4, which may be characterized as follows:

Dysbindin-1A is the full-length isoform, the mouse ortholog of which was the first dysbindin protein identified.5 This is the protein meant when ''dysbindin'' is used without qualification. Dysbindin-1A is a 351 aa protein in humans; orthologs in other species are 339-362 aa in length. Such orthologs have been identified not only in humans and mice, but also in the cow, pig, rat, chicken, frog, zebrafish, and amphioxus.

There is also some evidence for dysbindin-1A in sheep (NP_01119821) and the chimpanzee (XP_001169961) in the NCBI database. All known dysbindin-1A orthologs have one or more PEST domain at or near the end of the CTR

Dysbindin-1B is a 303 aa protein in humans and a 316 aa protein in frogs. It is essentially a CT-truncated version of dysbindin-1A with the added distinction of a markedly different C terminal sequence (aa 272-303 in humans and 272-316 in frogs) that lacks a PEST domain.

This does not illustrate a mouse protein of similar length (300 aa) identified by UniProt as dysbindin isoform 2 (Q91WZ8-2), which is merely mouse dysbindin-1A missing amino acids 170 through 220. It should not be wrongly identified for an ortholog of human dysbindin-1B.

We exclude it from the dysbindin protein family because it has no known transcript and no known orthologs in other species. There is no known mouse ortholog of human dysbindin-1B. A chimpanzee ortholog has been predicted from DNA in that species (XP_001169936 on NCBI).

The dysbindin protein found in the fruit fly Drosophila melanogaster known as CG6856-PA is tentatively classified here as an ortholog of dysbindin-1B. The aa sequence of its CCD is significantly related to that of CCDs in all known orthologs of dysbindin-1A and -1B. But the CTR of CG6856-PA is short (50 aa versus 161-181 aa in dysbindin-1A orthologs), and it lacks a PEST domain like dysbindin-1B.

Dysbindin-1C is a 270 aa protein in humans and a 271 aa protein in mice. In both species, it lacks an NTR and thus begins with the CCD. It is otherwise identical to dysbindin-1A, but not a degradation product of that isoform since it is the product of a different mRNA.

While the first promoter in DTNBP1 probably drives transcription for dysbindin-1A, the second promoter in that gene may drive transcription for dysbindin-1C. At the end of the CTR in both these isoforms is a clear PEST domain.

Gene Mapping

Dysbindin-1 is encoded by the DTNBP1 gene at chromosome locus 6p22.3 in humans. It has been found in both invertebrates and all vertebrates studied to date.

Gene Function

Dysbindin-1 may have diverse functions. Among these are the promotion of cell growth and proliferation, protection against neuronal apoptosis, facilitation of axon, dendrite, and dendritic spine growth, regulation of AP-3 cargo transport to lysosome-related organelles (including reserve pool synaptic vesicles), facilitation of glutamate release and inhibition of dopamine release, regulation of constitutive D2R cell surface expression, and promotion of cognitive processes.

Clinical Relevance

Variation in the gene encoding dysbindin-1 such as dystrobrevin-binding protein 1: DTNBP1 has frequently been associated with schizophrenia. Several studies have also found that dysbindin-1 gene and protein expression are altered in two affected brain areas in that disorder. Examples of these areas are the dorsolateral prefrontal cortex and the hippocampal formation.

Schizophrenia is an inherited illness for which there is no known cause and no specific and sensitive biological evidence of illness for diagnosis and treatment. Schizophrenia is a severe, chronic disorder, in which individuals afflicted with, experience hallucinations, delusions, disorganized thinking, and a decline in social functioning. Although the etiology is unknown, schizophrenia is currently hypothesized to be a neurodevelopmental disorder, as well as a disease of aberrant synaptic connectivity. Heredity is known to play a strong role in schizophrenia, and multiple genes of small effect interacting with environmental factors are believed to contribute to this illness.

Schizophrenia is associated with greater co-morbidity and lowered life expectancy. The disease process, anti-psychotic interventions, and socioeconomics foster very unhealthy habits such as poor diet, smoking, drug abuse as well as diseases. Such examples are obesity, diabetes, hyperlipidemia and cataracts. These factors contribute to an overall decline in health, interfere with clinical management, and place a strain on the medical infrastructure.

While the association between genetic variation in DTNBP1 and schizophrenia has been questioned recently, there is mounting evidence that the associations found reflect actual susceptibility variants in the gene. Even in the absence of such variants, altered dysbindin-1 gene and protein expression have been found in the dorsolateral prefrontal cortex and hippocampal formation of schizophrenia cases.

These changes may contribute to the pathophysiology of the disorder by altering brain development, dopaminergic and glutamatergic transmission, functional connectivity of neuronal populations in the cerebral cortical and the hippocampal formation, and cognition.

Clinical Impact of Study of the Gene

The absence of animal models to reproduce all aspects of schizophrenia makes the study of human brains from patients suffering from this psychiatric illness essential to advance our knowledge of its underlying pathology. Studies using neuroimaging of patients with schizophrenia, although extremely helpful and informative, do not inform molecular and cellular aspects of this illness.

Although schizophrenia-like behaviours were shown in hypothesis-driven genetic mouse models, particularly via disrupted DA or glutamine neurotransmission, cognitive ability and emotional intelligence is difficult to test in animal models. Nonetheless, neuroelectrophysiology is a promising tool for clinically testing schizophrenic patients and animal models with schizophrenia-like abnormal information processing.6

Proteomic utilities have just begun to define schizophrenia with molecular biology detail. Conventional modalities in proteomics have restrictive limitations, preventing the interrogation of proteins under a certain molecular weight such as the majority of neuropeptides, those found in or associated with the plasma membrane, an example is GPI anchored proteins, and the post-translation modifications heavily employed in brain tissue.

Ultimately, technology provides insight into only a small portion of the proteome. However, advances in mass spectrometric measures, namely tandem MS technology, offer the potential to identify and characterize novel biomarkers.

Schizophrenia remains a disabling condition, but progress in the genomic and proteomic sciences, more efficacious pharmacology for negative symptoms and cognitive dysfunction, and greater societal awareness and appreciation of mental health issues may help alleviate this problem.

The discovery of schizophrenia biomarkers will likely revolutionize the field of psychiatry, as did the introduction of psycho-pharmaceuticals, but such progress is still substantially in the future.

An animal model of impaired gamma band oscillation (GBO) which resembles the deficits seen in schizophrenia patients would be very useful as another measure to test current or novel pharmacological treatments. Evaluation of transgenic or knockout mouse lines for the presence of GBO abnormalities would also add another level of depth to those models.

In order to facilitate detection of genetic factors linked to schizophrenia, Kenneth Kendler and Dermot Walsh recruited members of families in Ireland with a history of the disorder.7 The fieldwork on this project, known as the Irish Study of High-Density Schizophrenia Families was completed by 1992.

Of the 1,770 individuals in the study, 1,480 in 265 families served as a linkage sample, so called because its members supplied both the DNA and adequate clinical records needed for genetic linkage analyses. Such analyses by Straub et al.8 soon showed linkage of chromosome region 6p24-22 with schizophrenia. Fine mapping of this linkage region in the Irish sample by Straub et al.8 yielded strong, family based evidence for association of multiple SNPs in (and three-SNP haplotypes of) DTNBP1 with schizophrenia.

Subsequent analysis of the same genotyped data set led to the report of a single risk haplotype consisting of eight SNPs in a 30.1 kb block of DTNBP1 covering introns 1.9

By mid 2009, there were 31 published studies testing association of DTNBP1 variants with schizophrenia in samples on four continents. Eighteen of those studies reported significant association in one or more sample. They found relatively common SNPs and/or combinations of them (haplotypes) in DTNBP1 significantly associated with schizophrenia.

Most of these variants were reported to confer increased risk of schizophrenia, but five studies also reported haplotypes conferring protection against (i.e., reduced risk for) the disorder .10 Except for two SNPs in the first promoter regions, all SNPs in DTNBP1 thus far associated with schizophrenia are in introns.11

No schizophrenia cases have been found to harbour deletion or insertion mutations in promoters or exons of DTNBP1.11 Despite the many positive association studies, doubts have been raised by some groups about DTNBP1 as a susceptibility gene for schizophrenia.

There are three major reasons given for these doubts. First, the positive studies often differ in the specific SNPs or haplotypes found to be associated with the disorder. Second, there have been 12 follow-up studies that failed to find an association of any SNPs in DTNBP1 with schizophrenia.

The largest of these negative studies are those of Sanders et al.12 on 1870 Caucasian cases of European ancestry and Sullivan et al.13 on 738 cases of European, African, or other ancestry. These studies found no link between schizophrenia and any of the 15 DTNBP1 SNPs associated with the disorder in one or more of the earlier studies. Third, no association has been found between a wide variety of SNPs in DTNBP1 and pre-morbid adjustment in adult-onset schizophrenia.

In a more recent study done by Ann Van Den Bogaert et al, their research findings suggests that genetic variation in the dysbindin gene is particularly involved in the development of schizophrenia in cases with a familial loading of the disease.

As Schizophrenia was assiociated with the gene for dystrobrevin-binding protein 1 (DTNBP1), three samples of subjects with schizophrenia and unaffected control subjects of German (418 cases, 285 controls), Polish (294 cases, 113 controls), and Swedish (142 cases, 272 controls) descent.14 They analyzed five single-nucleotide polymorphisms (P1635, P1325, P1320, P1757, and P1578) and identified significant evidence of association in the Swedish sample but not in those from Germany or Poland.

The results in the Swedish sample became even more significant after a separate analysis of those cases with a positive family history of schizophrenia, in whom the five-marker haplotype A-C-A-T-T showed a P value of .00009 (3.1% in controls, 17.8% in cases; OR 6.75; P p .00153 after Bonferroni correction) suggesting that genetic variation in the dysbindin gene is particularly involved in the development of schizophrenia in cases with a familial loading of the disease.14

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