The genetics and biology of DISC1--an emerging role in psychosis and cognition.
ABSTRACT In the developing field of biological psychiatry, DISC1 stands out by virtue of there being credible evidence, both genetic and biological, for a role in determining susceptibility to schizophrenia and related disorders. We highlight the methodologic paradigm that led to identification of DISC1 and review the supporting genetic and biological evidence. The original finding of DISC1 as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression has sparked a number of confirmatory linkage and association studies. These indicate that DISC1 is a generalizable genetic risk factor for psychiatric illness that also influences cognition in healthy subjects. DISC1 has also been shown to interact with a number of proteins with neurobiological pedigrees, including Ndel1 (NUDEL), a key regulator of neuronal migration with endo-oligopeptidase activity, and PDE4B, a phosphodiesterase that is critical for cyclic adenosine monophosphate signaling and that is directly linked to learning, memory, and mood. Both are potential "drug" targets. DISC1 has thus emerged as a key molecular player in the etiology of major mental illness and in normal brain processes.
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ABSTRACT: Despite intensive research over many years, the treatment of schizophrenia remains a major health issue. Current and emerging treatments for schizophrenia are based upon the classical dopamine and glutamate hypotheses of disease. Existing first and second generation antipsychotic drugs based upon the dopamine hypothesis are limited by their inability to treat all symptom domains and their undesirable side effect profiles. Third generation drugs based upon the glutamate hypothesis of disease are currently under evaluation but are more likely to be used as add on treatments. Hence there is a large unmet clinical need. A major challenge in neuropsychiatric disease research is the relative limited knowledge of disease mechanisms. However, as our understanding of the genetic causes of the disease evolves, novel strategies for the development of improved therapeutic agents will become apparent. In this review we consider the current status of knowledge of the genetic basis of schizophrenia, including methods for identifying genetic variants associated with the disorder and how they impact on gene function. Although the genetic architecture of schizophrenia is complex, some targets amenable to pharmacological intervention can be discerned. We conclude that many challenges lie ahead but the stratification of patients according to biobehavioural constructs that cross existing disease classifications but with common genetic and neurobiological bases, offer opportunities for new approaches to effective drug discovery.Pharmacology [?] Therapeutics 07/2014; · 7.79 Impact Factor
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ABSTRACT: IMPORTANCE One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation. OBJECTIVE To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals. DESIGN, SETTING, AND PARTICIPANTS Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals. MAIN OUTCOMES AND MEASURES We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts. RESULTS The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10-10). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10-9). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects. CONCLUSIONS AND RELEVANCE The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.JAMA Psychiatry 04/2014; · 12.01 Impact Factor
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ABSTRACT: Nuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1). Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In present study, we first investigated the expression of NDEL1 and its binding protein DISC1 after pilocarpine-induced epilepsy in male C57BL/6 mice. Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole hippocampus increased during the spontaneous seizure period after status epilepticus (SE). Interestingly, however, the expression of NDEL1 was decreased in the cornu ammonis 3 (CA3) and dentate gyrus (DG) regions. Moreover, SE also increased the number of blood vessels that fed the CA3 and DG regions of the hippocampus and increased the incidence of abnormalities in capillary network formation where NDEL1 protein was expressed positively. Meanwhile, the expression of phosphorylated ERK (p-ERK) was also increased during the spontaneous seizure period, with a similar expression pattern as NDEL1 and DISC1. Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE.Neuroscience 03/2014; · 3.12 Impact Factor