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Valderrama-Mantilla AI, Martín-Cuevas C, Gómez-Garrido A, Morente-Montilla C, Crespo-Facorro B, García-Cerro S. Shared molecular signature in Alzheimer's disease and schizophrenia: A systematic review of the reelin signaling pathway. Neurosci Biobehav Rev 2025; 169:106032. [PMID: 39894421 DOI: 10.1016/j.neubiorev.2025.106032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/21/2025] [Accepted: 01/26/2025] [Indexed: 02/04/2025]
Abstract
The Reelin signaling pathway, particularly the RELN-APOER2-DAB1 complex, has emerged as a key contributor to the neuropathology of Alzheimer's disease (AD) and Schizophrenia (SZ). Despite being distinct clinical conditions, these disorders exhibit similar patterns of cognitive decline, including early disruptions in synaptic function and memory impairments. Notably, individuals with SZ have a 2-4 fold increased risk of developing AD or other dementias, highlighting potential shared molecular mechanisms, and positioning Reelin as a pivotal link between them. This systematic review explores the role of Reelin and its signaling components across these disorders. In AD, Reelin disruption correlates with hallmark features such as Tau hyperphosphorylation, amyloid-beta accumulation, and cognitive deficits. In SZ, alterations in Reelin signaling, including epigenetic modifications affecting RELN expression, are linked to disruptions in neuronal development and synaptic plasticity, particularly in the parietal and prefrontal cortices. Additionally, genomic studies reveal specific RELN variants and allelic imbalances that may influence disease severity and treatment response in SZ, suggesting RELN's role as a potential biomarker for therapeutic outcomes. Region-specific Reelin alterations in both AD and SZ suggest differing impacts yet underscore a potential common molecular origin. Our findings highlight the Reelin pathway as a molecular convergence point, warranting further investigation as a therapeutic and diagnostic target for AD, SZ, and potentially other neuropsychiatric disorders. The interplay between genetic and epigenetic regulation of RELN may provide novel insights into neurodegeneration, with implications for personalized intervention strategies in AD and SZ.
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Affiliation(s)
| | - Celia Martín-Cuevas
- Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville 41013, Spain; Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid 28029, Spain.
| | - Ana Gómez-Garrido
- Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville 41013, Spain; Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid 28029, Spain.
| | - Cristina Morente-Montilla
- Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville 41013, Spain.
| | - Benedicto Crespo-Facorro
- Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville 41013, Spain; Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid 28029, Spain; Department of Psychiatry, School of Medicine, University of Seville, Manuel Siurot AV, Seville 41013, Spain.
| | - Susana García-Cerro
- Instituto de Biomedicina de Sevilla (IBiS)/University Hospital Virgen del Rocío/CSIC/University of Sevilla, Manuel Siurot AV, Seville 41013, Spain; Spanish Network for Research in Mental Health (CIBERSAM, ISCIII), Monforte de Lemos AV, 3-5, Madrid 28029, Spain.
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Joly-Amado A, Kulkarni N, Nash KR. Reelin Signaling in Neurodevelopmental Disorders and Neurodegenerative Diseases. Brain Sci 2023; 13:1479. [PMID: 37891846 PMCID: PMC10605156 DOI: 10.3390/brainsci13101479] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/13/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Reelin is an extracellular matrix glycoprotein involved in neuronal migration during embryonic brain development and synaptic plasticity in the adult brain. The role of Reelin in the developing central nervous system has been extensively characterized. Indeed, a loss of Reelin or a disruption in its signaling cascade leads to neurodevelopmental defects and is associated with ataxia, intellectual disability, autism, and several psychiatric disorders. In the adult brain, Reelin is critically involved in neurogenesis and synaptic plasticity. Reelin's signaling potentiates glutamatergic and GABAergic neurotransmission, induces synaptic maturation, and increases AMPA and NMDA receptor subunits' expression and activity. As a result, there is a growing literature reporting that a loss of function and/or reduction of Reelin is implicated in numerous neurodegenerative diseases. The present review summarizes the current state of the literature regarding the implication of Reelin and Reelin-mediated signaling during aging and neurodegenerative disorders, highlighting Reelin as a possible target in the prevention or treatment of progressive neurodegeneration.
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Affiliation(s)
- Aurelie Joly-Amado
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA; (N.K.); (K.R.N.)
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Chaves Filho AJM, Mottin M, Lós DB, Andrade CH, Macedo DS. The tetrapartite synapse in neuropsychiatric disorders: Matrix metalloproteinases (MMPs) as promising targets for treatment and rational drug design. Biochimie 2022; 201:79-99. [PMID: 35931337 DOI: 10.1016/j.biochi.2022.07.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 06/26/2022] [Accepted: 07/26/2022] [Indexed: 02/06/2023]
Abstract
Inflammation and an exacerbated immune response are widely accepted contributing mechanisms to the genesis and progression of major neuropsychiatric disorders. However, despite the impressive advances in understanding the neurobiology of these disorders, there is still no approved drug directly linked to the regulation of inflammation or brain immune responses. Importantly, matrix metalloproteinases (MMPs) comprise a group of structurally related endopeptidases primarily involved in remodeling extracellular matrix (ECM). In the central nervous system (CNS), these proteases control synaptic plasticity and strength, patency of the blood-brain barrier, and glia-neuron interactions through cleaved and non-cleaved mediators. Several pieces of evidence have pointed to a complex scenario of MMPs dysregulation triggered by neuroinflammation. Furthermore, major psychiatric disorders' affective symptoms and neurocognitive abnormalities are related to MMPs-mediated ECM changes and neuroglia activation. In the past decade, research efforts have been directed to broad-spectrum MMPs inhibitors with frustrating clinical results. However, in the light of recent advances in combinatorial chemistry and drug design technologies, specific and CNS-oriented MMPs modulators have been proposed as a new frontier of therapy for regulating ECM properties in the CNS. Therefore, here we aim to discuss the state of the art of MMPs and ECM abnormalities in major neuropsychiatric disorders, namely depression, bipolar disorder, and schizophrenia, the possible neuro-immune interactions involved in this complex scenario of MMPs dysregulation and propose these endopeptidases as promising targets for rational drug design.
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Affiliation(s)
- Adriano José Maia Chaves Filho
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Laboratory for Molecular Modeling and Drug Design - LabMol, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO, Brazil.
| | - Melina Mottin
- Laboratory for Molecular Modeling and Drug Design - LabMol, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | - Deniele Bezerra Lós
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Carolina Horta Andrade
- Laboratory for Molecular Modeling and Drug Design - LabMol, Faculty of Pharmacy, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | - Danielle S Macedo
- Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil
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Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
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Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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Sawahata M, Asano H, Nagai T, Ito N, Kohno T, Nabeshima T, Hattori M, Yamada K. Microinjection of Reelin into the mPFC prevents MK-801-induced recognition memory impairment in mice. Pharmacol Res 2021; 173:105832. [PMID: 34450306 DOI: 10.1016/j.phrs.2021.105832] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/16/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022]
Abstract
Reelin, a large extracellular matrix protein, helps to regulate neuronal plasticity and cognitive function. Several studies have shown that Reelin dysfunction, resulting from factors such as mutations in gene RELN or low Reelin expression, is associated with schizophrenia (SCZ). We previously reported that microinjection of Reelin into cerebral ventricle prevents phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear whether and how Reelin ameliorates behavioral abnormalities in the animal model of SCZ. In the present study, we evaluated the effect of recombinant Reelin microinjection into the medial prefrontal cortex (mPFC) on abnormal behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Microinjection of Reelin into the mPFC prevented impairment of recognition memory of MK-801-treated mice in the novel object recognition test (NORT). On the other hand, the same treatment had no effect on deficits in sensory-motor gating and short-term memory in the pre-pulse inhibition and Y-maze tests, respectively. To establish the neural substrates that respond to Reelin, the number of c-Fos-positive cells in the mPFC was determined. A significant increase in c-Fos-positive cells in the mPFC of MK-801-treated mice was observed when compared with saline-treated mice, and this change was suppressed by microinjection of Reelin into the mPFC. A K2360/2467A Reelin that cannot bind to its receptor failed to ameliorate MK-801-induced cognitive deficits in NORT. These results suggest that Reelin prevents MK-801-induced recognition memory impairment by acting on its receptors to suppress neural activity in the mPFC of mice.
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Affiliation(s)
- Masahito Sawahata
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan; Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Hiroki Asano
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Taku Nagai
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan; Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Japan
| | - Norimichi Ito
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takao Kohno
- Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, 467-8603, Japan
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Graduate School of Health Sciences, Fujita Health University, Toyoake 470-1192, Japan
| | - Mitsuharu Hattori
- Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, 467-8603, Japan
| | - Kiyofumi Yamada
- Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Aichi, Japan.
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Yin J, Lu Y, Yu S, Dai Z, Zhang F, Yuan J. Exploring the mRNA expression level of RELN in peripheral blood of schizophrenia patients before and after antipsychotic treatment. Hereditas 2020; 157:43. [PMID: 33158463 PMCID: PMC7648395 DOI: 10.1186/s41065-020-00158-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/28/2020] [Indexed: 01/10/2023] Open
Abstract
Background The Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR. Results The expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group. Conclusion The up-regulation of RELN mRNA expression was current in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.
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Affiliation(s)
- Jiajun Yin
- Brain Science Basic Laboratory, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, 156 Qianrong Road, Wuxi, 214151, Jiangsu Province, P.R. China
| | - Yana Lu
- Department of Psychiatry, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, Wuxi, Jiangsu Province, China
| | - Shui Yu
- Brain Science Basic Laboratory, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, 156 Qianrong Road, Wuxi, 214151, Jiangsu Province, P.R. China
| | - Zhanzhan Dai
- Department of Psychiatry, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, Wuxi, Jiangsu Province, China
| | - Fuquan Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, 264 Guangzhou Road, Nanjing, 210029, Jiangsu Province, P.R. China.
| | - Jianmin Yuan
- Brain Science Basic Laboratory, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, 156 Qianrong Road, Wuxi, 214151, Jiangsu Province, P.R. China.
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Association between RELN polymorphisms and schizophrenia in a Han population from Northeast China. Psychiatr Genet 2019; 29:232-236. [PMID: 31469785 DOI: 10.1097/ypg.0000000000000235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To explore the association between the RELN gene and schizophrenia in the overall sample and samples stratified by sex in a northeastern Chinese population. METHODS A total of 1536 participants from Jilin Province, China, were recruited in this case-control study. Four single nucleotide polymorphisms (rs1062831, rs3808039, rs362746, and rs736707) in the RELN gene were genotyped. Binary logistic regression analysis was applied to detect associations between the genotypes of each single nucleotide polymorphism and schizophrenia. P values of no more than 0.003125 [0.05/(4 SNPs*4 different genetic models)] after Bonferroni correction were considered statistically significant. RESULTS All single-nucleotide polymorphisms conformed to Hardy-Weinberg equilibrium in the control group. Logistic regression analysis revealed that after Bonferroni correction, rs362746 was associated with schizophrenia under the recessive model (P = 0.001) and codominant model (P = 0.003) in the overall group. The association between schizophrenia and RELN single-nucleotide polymorphisms was not found in a sex-specific pattern after Bonferroni correction. CONCLUSION Our study provides and supports the evidence that RELN is a candidate gene for schizophrenia. Replication studies conducted in different populations are required, and the sex-specific association of this gene with schizophrenia warrants further exploration.
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Luo X, Chen S, Xue L, Chen JH, Shi YW, Zhao H. SNP Variation of RELN Gene and Schizophrenia in a Chinese Population: A Hospital-Based Case-Control Study. Front Genet 2019; 10:175. [PMID: 30891068 PMCID: PMC6413413 DOI: 10.3389/fgene.2019.00175] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 02/18/2019] [Indexed: 02/05/2023] Open
Abstract
Aims: We aimed to explore whether RELN contributes to the vulnerability and severity of clinical symptoms of schizophrenia (SZ) in a Chinese population. Methods: The following were conducted in an adult Han Chinese population from southern China: case-control association analyses of 30 representative single nucleotide polymorphisms (SNPs) that were screened according to specific programs based on bioinformatics tools and former research and quantitative trait locus analyses with SNPs and psychiatric symptoms evaluated with the positive and negative symptoms scale. Results: A 4-SNP haplotype consisting of rs362814, rs39339, rs540058, and rs661575 was found to be significantly associated with SZ even after Bonferroni correction (χ2 = 29.024, p = 6.42E-04, p Bonf = 0.017), and the T-C-T-C haplotype was a protective factor for SZ (OR = 0.050, 95% CI = 0.004-0.705). Moreover, the 4-SNP haplotype showed a significant association with G16 (active social avoidance) after false discovery rate correction (χ2 = 28.620, p = 1.697E-04, p FDR = 0.025). In addition, P7 (hostility) was related to the haplotype comprising rs2229864, rs2535764, and rs262355 (χ2 = 31.424, p = 2.103E-05, p adjustment = 0.019) in quantitative trait loci analyses. Conclusion: Overall, this study showed several positive associations between RELN and SZ, as well as psychiatric symptoms, which not only supports the proposition that RELN is a susceptibility gene for SZ but also provides information on a genotype-phenotype correlation for SZ in a Chinese population.
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Affiliation(s)
- Xia Luo
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, China
- Department of Psychiatry, Shantou University Medical College, Shantou, China
| | - Si Chen
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Li Xue
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- *Correspondence: Jian-Huan Chen, Yan-Wei Shi, Hu Zhao,
| | - Yan-Wei Shi
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Jian-Huan Chen, Yan-Wei Shi, Hu Zhao,
| | - Hu Zhao
- Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Jian-Huan Chen, Yan-Wei Shi, Hu Zhao,
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Kara B, Sahin N, Kara M, Sakalli Cetin E, Topal H. The relationship between attention deficit hyperactivity disorder and reelin gene polymorphisms in Turkish population. PSYCHIAT CLIN PSYCH 2018. [DOI: 10.1080/24750573.2018.1478192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Affiliation(s)
- Bilge Kara
- Faculty of Medicine, Department of Psychiatry, Mugla Sitki Kocman University, Mugla, Turkey
| | - Nilfer Sahin
- Faculty of Medicine, Department of Child and Adolescent Psychiatry, Mugla Sitki Kocman University, Mugla, Turkey
| | - Murat Kara
- Faculty of Medicine, Department of Medical Genetics, Mugla Sitki Kocman University, Mugla, Turkey
| | - Esin Sakalli Cetin
- Faculty of Medicine, Department of Medical Biology, Mugla Sitki Kocman University, Mugla, Turkey
| | - Hatice Topal
- Faculty of Medicine, Department of Pediatrics, Mugla Sitki Kocman University, Mugla, Turkey
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Molinard-Chenu A, Dayer A. The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis. Biol Psychiatry 2018; 83:692-706. [PMID: 29305086 DOI: 10.1016/j.biopsych.2017.11.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 11/06/2017] [Accepted: 11/06/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Alterations in early steps of cortical circuit assembly are thought to play a critical role in vulnerability to schizophrenia (SZ), but the pathogenic impact of SZ-risk mutations on corticogenesis remains to be determined. DiGeorge syndrome critical region 2 (DGCR2) is located in the 22q11.2 locus, whose deletion is a major risk factor for SZ. Moreover, exome sequencing of individuals with idiopathic SZ identified a rare missense mutation in DGCR2, further suggesting that DGCR2 is involved in SZ. METHODS Here we investigated the function of Dgcr2 and the pathogenic impact of the SZ-risk DGCR2 mutation in mouse corticogenesis using in utero electroporation targeted to projection neurons. RESULTS Dgcr2 knockdown impaired radial locomotion and final translocation of projection neurons, leading to persistent laminar positioning alterations. The DGCR2 missense SZ-risk mutation had a pathogenic impact on projection neuron laminar allocation by reducing protein expression. Mechanistically, we identified Dgcr2 as a novel member of the Reelin complex, regulating the phosphorylation of Reelin-dependent substrates and the expression of Reelin-dependent transcriptional targets. CONCLUSIONS Overall, this study provides biological evidence that the SZ-risk gene DGCR2 regulates critical steps of early corticogenesis possibly through a Reelin-dependent mechanism. Additionally, we found that the SZ-risk mutation in DGCR2 has a pathogenic impact on cortical formation by reducing protein expression level, suggesting a functional role for DGCR2 haploinsufficiency in the 22q11.2 deletion syndrome.
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Affiliation(s)
- Aude Molinard-Chenu
- Department of Psychiatry, University of Geneva Medical School, Geneva, Switzerland; Department of Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva Medical Center, Geneva, Switzerland
| | - Alexandre Dayer
- Department of Psychiatry, University of Geneva Medical School, Geneva, Switzerland; Department of Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva Medical Center, Geneva, Switzerland.
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Gutiérrez-Malacatt H, Ayala-Sanchez M, Aquino-Ortega X, Dominguez-Rodriguez J, Martinez-Tovar A, Olarte-Carrillo I, Martinez-Hernandez A, C CCC, Orozco L, Cordova EJ. The rs61764370 Functional Variant in the KRAS Oncogene is Associated with Chronic Myeloid Leukemia Risk in Women. Asian Pac J Cancer Prev 2017; 17:2265-70. [PMID: 27221928 DOI: 10.7314/apjcp.2016.17.4.2265] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic myeloid leukemia (CML) is one of the most frequent hematopoietic malignancies in the elderly population; however, knowledge is limited regarding the genetic factors associated with increased risk for CML. Polymorphisms affecting microRNA (miRNA) biogenesis or mRNA:miRNA interactions are important risk factors in the development of different types of cancer. Thus, we carried out a case-control study to test the association with CML susceptibility of gene variants located in the miRNA machinery genes AGO1 (rs636832) and GEMIN4 (rs2740348), as well as in the miRNA binding sites of the genes BRCA1 (rs799917) and KRAS (rs61764370). MATERIALS AND METHODS We determined the genotype of 781 Mexican-Mestizo individuals (469 healthy subjects and 312 CML cases) for the four polymorphisms using TaqMan probes to test the association with CML susceptibility. RESULTS We found a borderline association of the minor homozygote genotype of the KRAS_rs61764370 polymorphism with an increased risk for CML susceptibility (P = 0.06). After gender stratification, this association was significant only for women (odds ratio [OR] = 13.41, P = 0.04). The distribution of the allelic and genotypic frequencies of the four studied SNPs was neither associated with advanced phases of CML nor treatment response. CONCLUSIONS To the best of our knowledge, this study is the first to show a significant association of the KRAS_rs61764370 SNP with CML. To further determine such an association of with CML susceptibility, our results must be replicated in different ethnic groups.
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Ishii K, Kubo KI, Nakajima K. Reelin and Neuropsychiatric Disorders. Front Cell Neurosci 2016; 10:229. [PMID: 27803648 PMCID: PMC5067484 DOI: 10.3389/fncel.2016.00229] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 09/22/2016] [Indexed: 12/22/2022] Open
Abstract
Proper neuronal migration and laminar formation during corticogenesis is essential for normal brain function. Disruption of these developmental processes is thought to be involved in the pathogenesis of some neuropsychiatric conditions. Especially, Reelin, a glycoprotein mainly secreted by the Cajal-Retzius cells and a subpopulation of GABAergic interneurons, has been shown to play a critical role, both during embryonic and postnatal periods. Indeed, animal studies have clearly revealed that Reelin is an essential molecule for proper migration of cortical neurons and finally regulates the cell positioning in the cortex during embryonic and early postnatal stages; by contrast, Reelin signaling is closely involved in synaptic function in adulthood. In humans, genetic studies have shown that the reelin gene (RELN) is associated with a number of psychiatric diseases, including Schizophrenia (SZ), bipolar disorder (BP) and autistic spectrum disorder. Indeed, Reln haploinsufficiency has been shown to cause cognitive impairment in rodents, suggesting the expression level of the Reelin protein is closely related to the higher brain functions. However, the molecular abnormalities in the Reelin pathway involved in the pathogenesis of psychiatric disorders are not yet fully understood. In this article, we review the current progress in the understanding of the Reelin functions that could be related to the pathogenesis of psychiatric disorders. Furthermore, we discuss the basis for selecting Reelin and molecules in its downstream signaling pathway as potential therapeutic targets for psychiatric illnesses.
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Affiliation(s)
- Kazuhiro Ishii
- Department of Anatomy, Keio University School of Medicine Tokyo, Japan
| | - Ken-Ichiro Kubo
- Department of Anatomy, Keio University School of Medicine Tokyo, Japan
| | - Kazunori Nakajima
- Department of Anatomy, Keio University School of Medicine Tokyo, Japan
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Identification of RELN variation p.Thr3192Ser in a Chinese family with schizophrenia. Sci Rep 2016; 6:24327. [PMID: 27071546 PMCID: PMC4829830 DOI: 10.1038/srep24327] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 03/24/2016] [Indexed: 12/11/2022] Open
Abstract
Schizophrenia (SCZ) is a serious psychiatric disease with strong heritability. Its complexity is reflected by extensive genetic heterogeneity and much of the genetic liability remains unaccounted for. We applied a combined strategy involving detection of copy number variants (CNVs), whole-genome mapping, and exome sequencing to identify the genetic basis of autosomal-dominant SCZ in a Chinese family. To rule out pathogenic CNVs, we first performed Illumina single nucleotide polymorphism (SNP) array analysis on samples from two patients and one psychiatrically healthy family member, but no pathogenic CNVs were detected. In order to further narrow down the susceptible region, we conducted genome-wide linkage analysis and mapped the disease locus to chromosome 7q21.13-22.3, with a maximum multipoint logarithm of odds score of 2.144. Whole-exome sequencing was then carried out with samples from three affected individuals and one unaffected individual in the family. A missense variation c.9575 C > G (p.Thr3192Ser) was identified in RELN, which is known as a risk gene for SCZ, located on chromosome 7q22, in the pedigree. This rare variant, as a highly penetrant risk variant, co-segregated with the phenotype. Our results provide genetic evidence that RELN may be one of pathogenic gene in SCZ.
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van den Berg SM, de Moor MHM, Verweij KJH, Krueger RF, Luciano M, Arias Vasquez A, Matteson LK, Derringer J, Esko T, Amin N, Gordon SD, Hansell NK, Hart AB, Seppälä I, Huffman JE, Konte B, Lahti J, Lee M, Miller M, Nutile T, Tanaka T, Teumer A, Viktorin A, Wedenoja J, Abdellaoui A, Abecasis GR, Adkins DE, Agrawal A, Allik J, Appel K, Bigdeli TB, Busonero F, Campbell H, Costa PT, Smith GD, Davies G, de Wit H, Ding J, Engelhardt BE, Eriksson JG, Fedko IO, Ferrucci L, Franke B, Giegling I, Grucza R, Hartmann AM, Heath AC, Heinonen K, Henders AK, Homuth G, Hottenga JJ, Iacono WG, Janzing J, Jokela M, Karlsson R, Kemp JP, Kirkpatrick MG, Latvala A, Lehtimäki T, Liewald DC, Madden PAF, Magri C, Magnusson PKE, Marten J, Maschio A, Mbarek H, Medland SE, Mihailov E, Milaneschi Y, Montgomery GW, Nauck M, Nivard MG, Ouwens KG, Palotie A, Pettersson E, Polasek O, Qian Y, Pulkki-Råback L, Raitakari OT, Realo A, Rose RJ, Ruggiero D, Schmidt CO, Slutske WS, Sorice R, Starr JM, St Pourcain B, Sutin AR, Timpson NJ, Trochet H, Vermeulen S, Vuoksimaa E, Widen E, Wouda J, Wright MJ, Zgaga L, Porteous D, Minelli A, Palmer AA, Rujescu D, Ciullo M, Hayward C, Rudan I, Metspalu A, Kaprio J, Deary IJ, Räikkönen K, Wilson JF, Keltikangas-Järvinen L, Bierut LJ, Hettema JM, Grabe HJ, Penninx BWJH, van Duijn CM, Evans DM, Schlessinger D, Pedersen NL, Terracciano A, McGue M, Martin NG, Boomsma DI. Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium. Behav Genet 2016; 46:170-82. [PMID: 26362575 PMCID: PMC4751159 DOI: 10.1007/s10519-015-9735-5] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 08/10/2015] [Indexed: 11/26/2022]
Abstract
Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.
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Affiliation(s)
- Stéphanie M van den Berg
- Department of Research Methodology, Measurement and Data-Analysis (OMD), Faculty of Behavioural, Management, and Social Sciences, University of Twente, PO Box 217, 7500 AE, Enschede, The Netherlands.
| | - Marleen H M de Moor
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
- Department of Clinical Child and Family Studies, VU University Amsterdam, Amsterdam, The Netherlands
- Department of Methods, VU University Amsterdam, Amsterdam, The Netherlands
| | - Karin J H Verweij
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Department of Developmental Psychology and EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, The Netherlands
| | - Robert F Krueger
- Department of Psychology, University of Minnesota, Minneapolis, USA
| | - Michelle Luciano
- Department of Psychology, University of Edinburgh, Edinburgh, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Alejandro Arias Vasquez
- Donders Institute for Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands
- Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | | | - Jaime Derringer
- Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Tõnu Esko
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | - Najaf Amin
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Scott D Gordon
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | | | - Amy B Hart
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
| | - Ilkka Seppälä
- Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland
| | - Jennifer E Huffman
- MRC Human Genetics Unit, MRC IGMM, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Bettina Konte
- Department of Psychiatry, University of Halle, Halle, Germany
| | - Jari Lahti
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
| | - Minyoung Lee
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Mike Miller
- Department of Psychology, University of Minnesota, Minneapolis, USA
| | - Teresa Nutile
- Institute of Genetics and Biophysics "A. Buzzati-Traverso" - CNR, Naples, Italy
| | | | - Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Alexander Viktorin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Juho Wedenoja
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Abdel Abdellaoui
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | - Goncalo R Abecasis
- Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Daniel E Adkins
- Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA
| | - Arpana Agrawal
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Jüri Allik
- Department of Psychology, University of Tartu, Tartu, Estonia
- Estonian Academy of Sciences, Tallinn, Estonia
| | - Katja Appel
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Timothy B Bigdeli
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Fabio Busonero
- Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy
| | - Harry Campbell
- Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
| | - Paul T Costa
- Behavioral Medicine Research Center, Duke University School of Medicine, Durham, NC, USA
| | - George Davey Smith
- Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Gail Davies
- Department of Psychology, University of Edinburgh, Edinburgh, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Harriet de Wit
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, USA
| | - Jun Ding
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Barbara E Engelhardt
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - Johan G Eriksson
- Folkhälsan Research Center, Helsinki, Finland
- National Institute for Health and Welfare (THL), Helsinki, Finland
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
- Unit of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
- Vasa Central Hospital, Vaasa, Finland
| | - Iryna O Fedko
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | | | - Barbara Franke
- Donders Institute for Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, The Netherlands
- Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Ina Giegling
- Department of Psychiatry, University of Halle, Halle, Germany
| | - Richard Grucza
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Andrew C Heath
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Kati Heinonen
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
| | | | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
| | - Jouke-Jan Hottenga
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | - William G Iacono
- Department of Psychology, University of Minnesota, Minneapolis, USA
| | - Joost Janzing
- Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Markus Jokela
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
| | - Robert Karlsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - John P Kemp
- Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
- Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Australia
| | - Matthew G Kirkpatrick
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, USA
| | - Antti Latvala
- Department of Public Health, University of Helsinki, Helsinki, Finland
- National Institute for Health and Welfare (THL), Helsinki, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland
| | - David C Liewald
- Department of Psychology, University of Edinburgh, Edinburgh, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Pamela A F Madden
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - Chiara Magri
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Patrik K E Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jonathan Marten
- MRC Human Genetics Unit, MRC IGMM, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Andrea Maschio
- Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy
| | - Hamdi Mbarek
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | - Sarah E Medland
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Evelin Mihailov
- Estonian Genome Center, University of Tartu, Tartu, Estonia
- Department of Biotechnology, University of Tartu, Tartu, Estonia
| | - Yuri Milaneschi
- Department of Psychiatry, EMGO+ Institute, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | | | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Michel G Nivard
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | - Klaasjan G Ouwens
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | - Aarno Palotie
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Erik Pettersson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Ozren Polasek
- Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia
| | - Yong Qian
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Laura Pulkki-Råback
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
| | - Olli T Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
| | - Anu Realo
- Department of Psychology, University of Tartu, Tartu, Estonia
| | - Richard J Rose
- Department of Psychological & Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Daniela Ruggiero
- Institute of Genetics and Biophysics "A. Buzzati-Traverso" - CNR, Naples, Italy
| | - Carsten O Schmidt
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Wendy S Slutske
- Department of Psychological Sciences and Missouri Alcoholism Research Center, University of Missouri, Columbia, MO, USA
| | - Rossella Sorice
- Institute of Genetics and Biophysics "A. Buzzati-Traverso" - CNR, Naples, Italy
| | - John M Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
| | - Beate St Pourcain
- Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
- School of Oral and Dental Sciences, University of Bristol, Bristol, UK
- School of Experimental Psychology, University of Bristol, Bristol, UK
| | - Angelina R Sutin
- National Institute on Aging, NIH, Baltimore, MD, USA
- College of Medicine, Florida State University, Tallahassee, FL, USA
| | - Nicholas J Timpson
- Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Holly Trochet
- MRC Human Genetics Unit, MRC IGMM, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Sita Vermeulen
- Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eero Vuoksimaa
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Elisabeth Widen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Jasper Wouda
- Department of Research Methodology, Measurement and Data-Analysis (OMD), Faculty of Behavioural, Management, and Social Sciences, University of Twente, PO Box 217, 7500 AE, Enschede, The Netherlands
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
| | | | - Lina Zgaga
- Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
- Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland
| | - David Porteous
- Medical Genetics Section, Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, UK
| | - Alessandra Minelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Abraham A Palmer
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, USA
| | - Dan Rujescu
- Department of Psychiatry, University of Halle, Halle, Germany
| | - Marina Ciullo
- Institute of Genetics and Biophysics "A. Buzzati-Traverso" - CNR, Naples, Italy
| | - Caroline Hayward
- MRC Human Genetics Unit, MRC IGMM, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Igor Rudan
- Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
| | - Andres Metspalu
- Estonian Genome Center, University of Tartu, Tartu, Estonia
- Estonian Academy of Sciences, Tallinn, Estonia
| | - Jaakko Kaprio
- Department of Public Health, University of Helsinki, Helsinki, Finland
- National Institute for Health and Welfare (THL), Helsinki, Finland
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Ian J Deary
- Department of Psychology, University of Edinburgh, Edinburgh, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - Katri Räikkönen
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
| | - James F Wilson
- MRC Human Genetics Unit, MRC IGMM, Western General Hospital, University of Edinburgh, Edinburgh, UK
- Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
| | | | - Laura J Bierut
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| | - John M Hettema
- Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | - Hans J Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
- Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, Stralsund, Germany
| | - Brenda W J H Penninx
- Department of Psychiatry, EMGO+ Institute, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - David M Evans
- Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - David Schlessinger
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Antonio Terracciano
- Folkhälsan Research Center, Helsinki, Finland
- National Institute on Aging, NIH, Baltimore, MD, USA
| | - Matt McGue
- Department of Psychology, University of Minnesota, Minneapolis, USA
- Institute of Public Health, University of Southern Denmark, Odense, Denmark
| | | | - Dorret I Boomsma
- Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands
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15
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Ching AS, Ahmad-Annuar A. A Perspective on the Role of microRNA-128 Regulation in Mental and Behavioral Disorders. Front Cell Neurosci 2015; 9:465. [PMID: 26696825 PMCID: PMC4677093 DOI: 10.3389/fncel.2015.00465] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 11/16/2015] [Indexed: 12/18/2022] Open
Abstract
MiRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally. Over the past decade, misregulated miRNA pathways have been associated with various diseases such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. In this article, we aim to discuss the role played by miR-128 in neuropsychiatric disorders, and highlight potential target genes from an in silico analysis of predicted miR-128 targets. We also discuss the differences of target gene determination based on a bioinformatics or empirical approach. Using data from TargetScan and published reports, we narrowed the miR-128 target gene list to those that are known to be associated with neuropsychiatric disorders, and found that these genes can be classified into 29 gene clusters and are mostly enriched in cancer and MAPK signaling pathways. We also highlight some recent studies on several of the miR-128 targets which should be investigated further as potential candidate genes for therapeutic interventions.
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Affiliation(s)
- Ai-Sze Ching
- Department of Biomedical Science, Faculty of Medicine, University of Malaya Kuala Lumpur, Malaysia
| | - Azlina Ahmad-Annuar
- Department of Biomedical Science, Faculty of Medicine, University of Malaya Kuala Lumpur, Malaysia
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Evaluating the relationship between reelin gene variants (rs7341475 and rs262355) and schizophrenia: A meta-analysis. Neurosci Lett 2015; 609:42-7. [PMID: 26455866 DOI: 10.1016/j.neulet.2015.10.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 09/09/2015] [Accepted: 10/05/2015] [Indexed: 11/23/2022]
Abstract
Studies have suggested that reelin (RELN) polymorphism was associated with the susceptibility of schizophrenia (SZ), but the results remained controversial. Thus, we conducted this meta-analysis to determine whether RELN variants (rs7341475 and rs262355) were associated with SZ risk. Studies were identified through retrieving Web of Science, PubMed and Embase databases from inception to May 2015. The genotype data were extracted to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). For rs7341475, five studies with 4741 SZ patients and 10075 controls are included and the results indicate that carriage of A allele is associated with decreased SZ risk in dominant genetic model (OR=0.90, 95%CI=0.83-0.98) and additive model (OR=0.90, 95% CI=0.84-0.97). Subgroup analysis indicates that the association between rs7341475 and SZ is only significant in Caucasian. For rs262355, four studies with 2017 SZ patients and 3274 controls are included, the results demonstrate that carriage of A allele is associated with increased risk of SZ only in Caucasian (dominant model: OR=1.17, 95%CI=1.01-1.37; additive model OR=1.13, 95%CI=1.02-1.27). This meta-analysis suggests that rs7341475 (A/G) and rs262355 (A/T) polymorphisms in RELN gene are inversely associated with SZ risk.
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Samsom JN, Wong AHC. Schizophrenia and Depression Co-Morbidity: What We have Learned from Animal Models. Front Psychiatry 2015; 6:13. [PMID: 25762938 PMCID: PMC4332163 DOI: 10.3389/fpsyt.2015.00013] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/24/2015] [Indexed: 12/15/2022] Open
Abstract
Patients with schizophrenia are at an increased risk for the development of depression. Overlap in the symptoms and genetic risk factors between the two disorders suggests a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. Understanding these shared mechanisms will be important in informing the development of new treatments. Rodent models are powerful tools for understanding gene function as it relates to behavior. Examining rodent models relevant to both schizophrenia and depression reveals a number of common mechanisms. Current models which demonstrate endophenotypes of both schizophrenia and depression are reviewed here, including models of CUB and SUSHI multiple domains 1, PDZ and LIM domain 5, glutamate Delta 1 receptor, diabetic db/db mice, neuropeptide Y, disrupted in schizophrenia 1, and its interacting partners, reelin, maternal immune activation, and social isolation. Neurotransmission, brain connectivity, the immune system, the environment, and metabolism emerge as potential common mechanisms linking these models and potentially explaining comorbid depression in schizophrenia.
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Affiliation(s)
- James N Samsom
- Department of Molecular Neuroscience, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute , Toronto, ON , Canada ; Department of Pharmacology, Faculty of Medicine, University of Toronto , Toronto, ON , Canada
| | - Albert H C Wong
- Department of Molecular Neuroscience, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute , Toronto, ON , Canada ; Department of Pharmacology, Faculty of Medicine, University of Toronto , Toronto, ON , Canada ; Department of Psychiatry, Faculty of Medicine, University of Toronto , Toronto, ON , Canada
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18
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Thom M, Kensche M, Maynard J, Liu J, Reeves C, Goc J, Marsdon D, Fluegel D, Foong J. Interictal psychosis following temporal lobe surgery: dentate gyrus pathology. Psychol Med 2014; 44:3037-3049. [PMID: 25065503 DOI: 10.1017/s0033291714000452] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND De novo interictal psychosis, albeit uncommon, can develop in patients following temporal lobe surgery for epilepsy. Pathological alterations of the dentate gyrus, including cytoarchitectural changes, immaturity and axonal reorganization that occur in epilepsy, may also underpin co-morbid psychiatric disorders. Our aim was to study candidate pathways that may be associated with the development of interictal psychosis post-operatively in patients with hippocampal sclerosis (HS). METHOD A total of 11 patients with HS who developed interictal psychosis (HS-P) post-operatively were compared with a matched surgical HS group without psychosis (HS-NP). Resected tissues were investigated for the extent of granule cell dispersion, mossy fibre sprouting and calbindin expression in the granule cells. We quantified doublecortin, mini-chromosome maintenance protein 2 (MCM2) and reelin-expressing neuronal populations in the dentate gyrus as well as the distribution of cannabinoid type 1 receptor (CBR1). RESULTS The patterns of neuronal loss and gliosis were similar in both groups. HS-P patients demonstrated less mossy fibre sprouting and granule cell dispersion (p < 0.01) and more frequent reduction in calbindin expression in granule cells. There were no group differences in the densities of immature MCM2, doublecortin and reelin-positive cells. CBR1 labelling was significantly lower in Cornu ammonis area CA4 relative to other subfields (p < 0.01); although reduced staining in all hippocampal regions was noted in HS-P compared with HS-NP patients, the differences were not statistically significant. CONCLUSIONS The alterations in dentate gyrus pathology found in HS-P patients could indicate underlying differences in the cellular response to seizures. These mechanisms may predispose to the development of psychosis in epilepsy and warrant further investigation.
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Affiliation(s)
- M Thom
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - M Kensche
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - J Maynard
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - J Liu
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - C Reeves
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - J Goc
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - D Marsdon
- Division of Neuropathology,National Hospital for Neurology and Neurosurgery,Queen Square, London WC1N 3BG,UK
| | - D Fluegel
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
| | - J Foong
- Department of Clinical and Experimental Epilepsy,University College London,Institute of Neurology, London,UK
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Peterson SM, Zhang J, Freeman JL. Developmental reelin expression and time point-specific alterations from lead exposure in zebrafish. Neurotoxicol Teratol 2013; 38:53-60. [PMID: 23665418 DOI: 10.1016/j.ntt.2013.04.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 04/22/2013] [Accepted: 04/24/2013] [Indexed: 11/19/2022]
Abstract
Reelin (RELN) is a large glycoprotein that plays critical roles during and after neuronal development. In a previous study utilizing developing zebrafish, the RELN ortholog was in a subset of genes associated with neuronal function that was altered following exposure to 100ppb Pb at 72h post-fertilization (hpf). Although RELN is associated with neurodevelopment and neurological diseases, it represents a previously uncharacterized target for developmental Pb neurotoxicity. To further investigate Pb-induced expression decrease of RELN, a more detailed analysis was done using in situ hybridization and quantitative PCR (qPCR) on developing zebrafish at multiple developmental time points and at different exposure concentrations. Time points included in the analysis were 24, 36, 48, 60, 72 and 96hpf. The four exposure conditions tested were 10, 50 or 100ppb Pb as well as a control. In situ hybridization demonstrated concentrated expression of the gene in the telencephalon and in midbrain, hindbrain and spinal cord. Expression was less spatially restricted early in development but became isolated to specific cell populations in the central nervous system by 48hpf. The telencephalon demonstrated a high degree of expression throughout development. Pb exposure did not affect the observed location of expression at any of the time points tested. However, qPCR analysis demonstrated that reln expression statistically decreased in embryos exposed to the highest concentration compared to controls at 60hpf. No changes in brain morphology as assessed by measuring brain length and no significant increase in the number of apoptotic cells in the brain were observed at the highest exposure concentration. These data demonstrate that a decrease in reln expression occurs following Pb exposure at a concentration below one that results in changes in brain length or in the number of apoptotic cells in the zebrafish model system during a short window and is likely linked to concurrent developmental processes.
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Affiliation(s)
- Samuel M Peterson
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
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Folsom TD, Fatemi SH. The involvement of Reelin in neurodevelopmental disorders. Neuropharmacology 2013; 68:122-35. [PMID: 22981949 PMCID: PMC3632377 DOI: 10.1016/j.neuropharm.2012.08.015] [Citation(s) in RCA: 200] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Revised: 08/14/2012] [Accepted: 08/16/2012] [Indexed: 12/21/2022]
Abstract
Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adulthood (maintenance of synaptic function). A number of neuropsychiatric disorders including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's disease and lissencephaly share a common feature of abnormal Reelin expression in the brain. Altered Reelin expression has been hypothesized to impair neuronal connectivity and synaptic plasticity, leading ultimately to the cognitive deficits present in these disorders. The mechanisms for abnormal Reelin expression in some of these disorders are currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, FMRP underexpression and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.
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Affiliation(s)
- Timothy D. Folsom
- Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN 55455, USA
| | - S. Hossein Fatemi
- Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN 55455, USA
- Department of Pharmacology, University of Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN 55455, USA
- Department of Neuroscience, University of Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN 55455, USA
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