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ABSTRACT: Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.
Frontiers in Biology. 02/2013; 8(1):1-31.
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ABSTRACT: Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.
Frontiers in biology. 02/2013; 8(1):1-31.
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Emma Sprooten,
Kathryn M Fleming, Pippa A Thomson,
Mark E Bastin,
Heather C Whalley,
Jeremy Hall,
Jess E Sussmann,
James McKirdy,
Douglas Blackwood,
Stephen M Lawrie,
Andrew M McIntosh
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ABSTRACT: White matter integrity, as measured using diffusion tensor imaging (DTI), is reduced in individuals with bipolar disorder (BD), their unaffected relatives and carriers of specific risk-alleles. Fractional anisotropy (FA), an index of white matter integrity, is highly heritable but the genetic architecture of this trait has received little investigation. In this study we performed a genome-wide association study with FA as quantitative phenotype, in unaffected relatives of patients with BD (N=70) and a matched control group (N=80). Amongst our top results were SNPs located in genes involved in cell adhesion, white matter development and neuronal plasticity. Pathway analysis of the top associated polymorphisms and genes confirmed the enrichment of processes relevant to BD and white matter development, including axon guidance, ErbB-signalling neurotrophin signalling, phosphatidylinositol signalling, and cell adhesion. The majority of genes implicated in these pathways were differentially associated with FA in individuals at high familial risk, suggesting interactions with genetic background or environmental factors secondary to familial risk for BD. Although the present findings require independent replication, the results encourage the use of global FA as a quantitative phenotype in future large-scale studies which may help to identify the biological processes underlying reduced FA in BD and other psychiatric disorders.
Psychiatry research. 12/2012;
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ABSTRACT: Mental disorders have a complex etiology resulting from interactions between multiple genetic risk factors and stressful life events. Orphan G protein-coupled receptor 50 (GPR50) has been identified as a genetic risk factor for bipolar disorder and major depression in women, and there is additional genetic and functional evidence linking GPR50 to neurite outgrowth, lipid metabolism, and adaptive thermogenesis and torpor. However, in the absence of a ligand, a specific function has not been identified. Adult GPR50 expression has previously been reported in brain regions controlling the HPA axis, but its developmental expression is unknown. In this study, we performed extensive expression analysis of GPR50 and three protein interactors using rt-PCR and immunohistochemistry in the developing and adult mouse brain. Gpr50 is expressed at embryonic day 13 (E13), peaks at E18, and is predominantly expressed by neurons. Additionally we identified novel regions of Gpr50 expression, including brain stem nuclei involved in neurotransmitter signaling: the locus coeruleus, substantia nigra, and raphe nuclei, as well as nuclei involved in metabolic homeostasis. Gpr50 colocalizes with yeast-two-hybrid interactors Nogo-A, Abca2, and Cdh8 in the hypothalamus, amygdala, cortex, and selected brain stem nuclei at E18 and in the adult. With this study, we identify a link between GPR50 and neurotransmitter signaling and strengthen a likely role in stress response and energy homeostasis.
ACS Chemical Neuroscience 06/2012; 3(6):459-72. · 3.68 Impact Factor
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Rosie M Walker,
Alison E Hill,
Alice C Newman,
Gillian Hamilton,
Helen S Torrance,
Susan M Anderson,
Fumiaki Ogawa,
Pelagia Derizioti,
Jérôme Nicod,
Sonja C Vernes,
Simon E Fisher, Pippa A Thomson,
David J Porteous,
Kathryn L Evans
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ABSTRACT: Disrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia. Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.
Human Molecular Genetics 03/2012; 21(13):2862-72. · 7.64 Impact Factor
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ABSTRACT: Variation in the complement receptor 1 gene (CR1) has been identified in recent genome-wide association studies as a risk factor for Alzheimer's disease. Here, we show that two Alzheimer's disease-associated CR1 variants, rs6656401 and rs3818361, are associated with major recurrent depression in females in a population-based cohort using individuals from the Generation Scotland: Scottish Family Health Study.
Neuroscience Letters 02/2012; 510(1):6-9. · 2.11 Impact Factor
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Andrew M McIntosh,
Arthur A Simen,
Kathryn L Evans,
Jeremy Hall,
Donald J Macintyre,
Douglas Blackwood,
Andrew D Morris,
Blair H Smith,
Anna Dominiczak,
David Porteous,
Hb Ian J Deary, Pippa A Thomson
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ABSTRACT: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1-4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.
Frontiers in genetics. 01/2012; 3:116.
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ABSTRACT: Nuclear distribution factor E-homolog 1 (NDE1), Lissencephaly 1 (LIS1), and NDE-like 1 (NDEL1) together participate in essential neurodevelopmental processes, including neuronal precursor proliferation and differentiation, neuronal migration, and neurite outgrowth. NDE1/LIS1/NDEL1 interacts with Disrupted in Schizophrenia 1 (DISC1) and the cAMP-hydrolyzing enzyme phosphodiesterase 4 (PDE4). DISC1, PDE4, NDE1, and NDEL1 have each been implicated as genetic risk factors for major mental illness. Here, we demonstrate that DISC1 and PDE4 modulate NDE1 phosphorylation by cAMP-dependent protein kinase A (PKA) and identify a novel PKA substrate site on NDE1 at threonine-131 (T131). Homology modeling predicts that phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions, which we confirm experimentally. DISC1-PDE4 interaction thus modulates organization of the NDE1/NDEL1/LIS1 complex. T131-phosphorylated NDE1 is present at the postsynaptic density, in proximal axons, within the nucleus, and at the centrosome where it becomes substantially enriched during mitosis. Mutation of the NDE1 T131 site to mimic PKA phosphorylation inhibits neurite outgrowth. Thus PKA-dependent phosphorylation of the NDE1/LIS1/NDEL1 complex is DISC1-PDE4 modulated and likely to regulate its neural functions.
Journal of Neuroscience 06/2011; 31(24):9043-54. · 7.11 Impact Factor
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Goultchira Chakirova,
Heather C Whalley, Pippa A Thomson,
William Hennah,
Thomas W J Moorhead,
Killian A Welch,
Stephen Giles,
Jeremy Hall,
Eve C Johnstone,
Stephen M Lawrie,
David J Porteous,
Verity J Brown,
Andrew M McIntosh
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ABSTRACT: Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n=33), patients with schizophrenia (n=20) and patients with bipolar disorder (n=36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group × genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.
Psychiatry Research 03/2011; 192(1):20-8. · 2.52 Impact Factor
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ABSTRACT: We re-annotated the interacting partners of the neuronal scaffold protein DISC1 using a knowledge-based approach that incorporated recent protein interaction data and published literature to. This revealed two highly connected networks. These networks feature cellular function and maintenance, and cell signaling. Of potentially greatest interest was the novel finding of a high degree of connectivity between the DISC1 scaffold protein, linked to psychiatric illness, and huntingtin, the protein which is mutated in Huntington's disease. The potential link between DISC1, huntingtin and their interacting partners may open new areas of research into the effects of pathway dysregulation in severe neurological disorders.
PLoS ONE 01/2011; 6(1):e16263. · 4.09 Impact Factor
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ABSTRACT: Schizophrenia and related disorders have a major genetic component. Several large-scale studies have uncovered a number of possible candidate genes, but these have yet to be consistently replicated and their underlying biological function remains elusive. One exception is 'Disrupted in schizophrenia 1' (DISC1), a gene locus originally identified in a large Scottish family, showing a heavy burden of major mental illnesses associated with a balanced t(1;11)(q42.1;q14.3) chromosome translocation. Substantial genetic and biological research on DISC1 has been reported in the intervening 10 years: DISC1 is now recognized as a genetic risk factor for a spectrum of psychiatric disorders and DISC1 impacts on many aspects of central nervous system (CNS) function, including neurodevelopment, neurosignaling, and synaptic functioning. Evidence has emerged from genetic studies showing a relationship between DISC1 and quantitative traits, including working memory, cognitive aging, gray matter volume in the prefrontal cortex, and abnormalities in hippocampal structures and function. DISC1 interacts with numerous proteins also involved in neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction, some of which have been reported as independent genetic susceptibility factors for psychiatric morbidity. Here, we focus on the growing literature relating genetic variation in the DISC1 pathway to functional and structural studies of the brain in humans and in the mouse.
Schizophrenia Bulletin 01/2011; 37(1):14-20. · 8.80 Impact Factor
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Rosie M Walker,
Andrea Christoforou, Pippa A Thomson,
Kevin A McGhee,
Alan Maclean,
Thomas W Mühleisen,
Jana Strohmaier,
Vanessa Nieratschker,
Markus M Nöthen,
Marcella Rietschel,
Sven Cichon,
Stewart W Morris,
Omer Jilani,
David Stclair,
Douglas H Blackwood,
Walter J Muir,
David J Porteous,
Kathryn L Evans
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ABSTRACT: Schizophrenia (SCZ) and bipolar disorder (BPD) are severe heritable psychiatric disorders involving a complex genetic aetiology. Neuregulin 1 (NRG1) is a leading candidate gene for SCZ, and has recently been implicated in BPD. We previously reported association of two NRG1 haplotypes with SCZ and BPD in a Scottish case-control sample. One haplotype is located at the 5' end of the gene (region A), and the other is located at the 3' end (region B). Here, association to haplotypes within regions A and B was assessed in patients with SCZ and BPD in a second Scottish case-control sample and in the two Scottish samples combined. Association to region B was also assessed in patients with SCZ and BPD in a German case-control sample, and in all three samples combined. No evidence was found for association in the new samples when analysed individually; however, in the joint analysis of the two Scottish samples, a region B haplotype comprising two SNPs (rs6988339 and rs3757930) was associated with SCZ and the combined case group (SCZ: p=0.0037, OR=1.3, 95% CI: 1.1-1.6; BPD+SCZ: p=0.0080, OR=1.2, 95% CI: 1.1-1.5), with these associations withstanding multiple testing correction at the single-test level (SCZ: p(st)=0.022; BPD+SCZ: p(st)=0.044). This study supports the involvement of NRG1 variants in the less well studied 3' region in conferring susceptibility to SCZ and BPD in the Scottish population.
Neuroscience Letters 06/2010; 478(1):9-13. · 2.11 Impact Factor
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ABSTRACT: A recent report detected association between GPR50, an orphan G protein-coupled receptor, and bipolar disorder (BD) in the Scottish population [29]. We sought to replicate this study in a second sample from the same population, consisting of 338 patients with BD, 359 patients with major depressive disorder (MDD) and 913 control individuals. In addition, the effect of GPR50 genotype on clinical phenotype and treatment response was assessed in a subset of 56 patients with early onset MDD (eoMDD). We identified an association with BD in women with an intronic SNP, rs1202874, that withstood correction for multiple testing (p=0.0035, permuted p=0.037, OR=1.9, 95%CI 1.2-3.0). However, we failed to find an association with the previously associated Delta502-505 polymorphism (p=0.2). Combined analysis of this and the original samples did detect association between the deletion and susceptibility to BD in females, but with a reduced effect size (p=0.0006, permuted p=0.0024, OR=1.41, 95%CI 1.16-1.71). In the highly phenotyped eoMDD subgroup, we found an association between the Delta502-505 deletion polymorphism and age of onset (p=0.049), number of episodes (p=0.044), hypomanic symptoms (p=0.019), and initial thinking time (p=0.027), in women; and in family history of depression in men (p=0.038), uncorrected for multiple testing. No association was seen between Delta502-505 genotype and treatment response at 3 months. To our knowledge this is the first association of rs1202874 with BD and is the second positive association at the GPR50 locus.
Neuroscience Letters 04/2010; 475(3):169-73. · 2.11 Impact Factor
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Stephanie Le Hellard,
Andrew J Lee,
Sarah Underwood, Pippa A Thomson,
Stewart W Morris,
Helen S Torrance,
Susan M Anderson,
Richard R Adams,
Pau Navarro,
Andrea Christoforou,
Lorna M Houlihan,
Sevilla Detera-Wadleigh,
Michael J Owen,
Philip Asherson,
Walter J Muir,
Douglas H R Blackwood,
Naomi R Wray,
David J Porteous,
Kathryn L Evans
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ABSTRACT: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region.
We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families.
We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families.
Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.
Biological Psychiatry 04/2007; 61(6):797-805. · 8.28 Impact Factor
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ABSTRACT: Depression is common in patients with schizophrenia and it is well established from family studies that rates of depression are increased among relatives of probands with schizophrenia, making it likely that the phenotypes described under the categories of affective and non-affective psychoses share some genetic risk factors. Family linkage studies have identified several chromosomal regions likely to contain risk genes for schizophrenia and bipolar disorder, suggesting common susceptibility loci. Candidate gene association studies have provided further evidence to suggest that some genes including two of the most studied candidates, Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may be involved in both types of psychosis. We have recently identified another strong candidate for a role in both schizophrenia and affective disorders, GRIK4 a glutamate receptor mapped to chromosome 11q23 [Glutamate Receptor, Ionotropic, Kainate, type 4]. This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association of GRIK4 with both schizophrenia and bipolar disorder. Identifying genes implicated in the psychoses may eventually provide the basis for classification based on biology rather than symptoms, and suggest novel treatment strategies for these complex brain disorders.
Neurotoxicity Research 02/2007; 11(1):73-83. · 3.51 Impact Factor
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Jeremy Hall,
Heather C Whalley,
Dominic E Job,
Ben J Baig,
Andrew M McIntosh,
Kathryn L Evans, Pippa A Thomson,
David J Porteous,
David G Cunningham-Owens,
Eve C Johnstone,
Stephen M Lawrie
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ABSTRACT: NRG1, encoding neuregulin 1, is a susceptibility gene for schizophrenia, but no functional mutation causally related to the disorder has yet been identified. Here we investigate the effects of a variant in the human NRG1 promoter region in subjects at high risk of schizophrenia. We show that this variant is associated with (i) decreased activation of frontal and temporal lobe regions, (ii) increased development of psychotic symptoms and (iii) decreased premorbid IQ.
Nature Neuroscience 01/2007; 9(12):1477-8. · 15.53 Impact Factor
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J Kirsty Millar,
Benjamin S Pickard,
Shaun Mackie,
Rachel James,
Sheila Christie,
Sebastienne R Buchanan,
M Pat Malloy,
Jennifer E Chubb,
Elaine Huston,
George S Baillie, Pippa A Thomson,
Elaine V Hill,
Nicholas J Brandon,
Jean-Christophe Rain,
L Miguel Camargo,
Paul J Whiting,
Miles D Houslay,
Douglas H R Blackwood,
Walter J Muir,
David J Porteous
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ABSTRACT: The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
Science 12/2005; 310(5751):1187-91. · 31.20 Impact Factor
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ABSTRACT: A balanced (1;11)(q42;q14) translocation co-segregates with schizophrenia and major affective disorders in a large Scottish family. The translocation breakpoint on chromosome 1 is located within the Disrupted in Schizophrenia 1 and 2 genes (DISC1 and DISC2). Consequently loss of normal function of these genes is likely to underlie the susceptibility to developing psychiatric disorders that is conferred by inheritance of the translocation. Additionally, a number of independent genetic studies highlight the region of chromosome 1q containing DISC1 and DISC2 as a likely susceptibility locus for both schizophrenia and affective disorders. These genes are thus implicated in the aetiology of major psychiatric disorders in several populations. Although the function of DISC1 was initially unknown, several recent reports have made significant progress towards understanding its role in the central nervous system. Intriguingly, all data obtained to date point towards an involvement in processes critical to neurodevelopment and function. DISC2 has not been studied in detail, but is likely to modulate DISC1 expression. Overall, it is clear from the combination of genetic and functional data that DISC1 and/or DISC2 are emerging as important factors in the molecular genetics of psychiatric illness.
Annals of Medicine 02/2004; 36(5):367-78. · 3.52 Impact Factor
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Genetics 03/2003; 163(2):833-5; author reply 837-8. · 4.01 Impact Factor
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ABSTRACT: G protein-coupled receptors (GPCRs) form a link between the cell and their environment when signalling pathways are activated upon ligand binding. However, the ligands and functions for many GPCRs remain to be determined. We sought to understand the function of one such orphan, G protein-coupled receptor 50 (GPR50), through identification of protein interactors. GPR50 was previously discovered as a candidate gene for psychiatric illness and lipid metabolism. Here, we identified neurite outgrowth inhibitor NOGO-A as an interacting partner of GPR50 by yeast two-hybrid studies. We confirmed the interaction in mammalian cells and found an enrichment of both Gpr50 and neuronal Nogo-A at the synapse. In contrast to neuronal NOGO-A overexpression, overexpression of GPR50 increased neurite length and filopodia- and lamellipodia-like structures in differentiated Neuroscreen-1 cells. The results are markedly similar to a recent study in Nogo-A KO mice and support the involvement of GPR50 in mental disorders with links to several disease mechanisms.
Molecular and Cellular Neuroscience.
