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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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Millat MS, Roy J, Rahman MA, Aziz MA, Islam S, Chowdhury MMI, Barek MA, Hussain MS, Uddin MS, Siddiqui SA, Islam MS. Association of NOTCH4 and CYP2E1 Genetic Variants With Schizophrenia in the Bangladeshi Population: A Case-Control Study. Health Sci Rep 2024; 7:e70262. [PMID: 39698532 PMCID: PMC11652386 DOI: 10.1002/hsr2.70262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 10/03/2024] [Accepted: 11/23/2024] [Indexed: 12/20/2024] Open
Abstract
Background and Aims Schizophrenia (SCZ) is among the most persistent and devastating psychological problems. Different genetic polymorphisms are responsible for the predisposition of SCZ, and we screened NOTCH4 (rs2071287, rs204993) and CYP2E1 (rs2070673) polymorphisms in this study to find the connection with SCZ development. Methods We investigated a total of 420 samples (210 patients and 210 controls) and used the PCR-RFLP technique to genotype all SNPs. For statistical analyses, SPSS (version 25.0) was applied. Results In the case of NOTCH4 rs2071287, no evidence of a link was found in any genetic models, whereas NOTCH4 rs204993 and CYP2E1 rs2070673 showed a significant linkage in four genetic models with SCZ risk (for NOTCH4 rs204993, additive model 2: OR = 3.39, CI = 1.84-6.23, p = 0.0001; dominant: OR = 1.84, CI = 1.22-2.76, p = 0.0032; recessive: OR = 2.67, CI = 1.53-4.64, p = 0.0005; allelic: OR = 1.75, CI = 1.32-2.30, p = 0.0001 and for CYP2E1 rs2070673, additive model 2: OR = 0.39, CI = 0.22-0.69, p = 0.0013; recessive: OR = 0.45, CI = 0.29-0.68, p = 0.0002; overdominant: OR = 1.49, CI = 1.02-2.19, p = 0.0408; allelic: OR = 0.61, CI = 0.46-0.80, p = 0.0004). Conclusions The findings of our study suggest that the polymorphisms NOTCH4 rs204993 and CYP2E1 rs2070673 in the Bangladeshi ethnicity are connected to the risk of SCZ.
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Affiliation(s)
- Md. Shalahuddin Millat
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Joysree Roy
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Md. Atikur Rahman
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Md. Abdul Aziz
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Safiqul Islam
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | | | - Md Abdul Barek
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Md. Saddam Hussain
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Mohammad Sarowar Uddin
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Shafayet Ahmed Siddiqui
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
| | - Mohammad Safiqul Islam
- Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of PharmacyNoakhali Science and Technology UniversitySonapurNoakhaliBangladesh
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Fuentealba LM, Pizarro H, Marzolo MP. OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses. Biomolecules 2024; 14:799. [PMID: 39062513 PMCID: PMC11274606 DOI: 10.3390/biom14070799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.
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Affiliation(s)
| | | | - María-Paz Marzolo
- Laboratorio de Tráfico Intracelular y Señalización, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 7810128, Chile; (L.M.F.); (H.P.)
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He Q, Li R, Zhong N, Ma J, Nie F, Zhang R. The role and molecular mechanisms of the early growth response 3 gene in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2024; 195:e32969. [PMID: 38327141 DOI: 10.1002/ajmg.b.32969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 01/15/2024] [Accepted: 01/22/2024] [Indexed: 02/09/2024]
Abstract
Schizophrenia is a chronic, debilitating mental illness caused by both genetic and environmental factors. Genetic factors play a major role in schizophrenia development. Early growth response 3 (EGR3) is a member of the EGR family, which is associated with schizophrenia. Accumulating studies have investigated the relationship between EGR3 and schizophrenia. However, the role of EGR3 in schizophrenia pathogenesis remains unclear. In the present review, we focus on the progress of research related to the role of EGR3 in schizophrenia, including association studies between EGR3 and schizophrenia, abnormal gene expressional analysis of EGR3 in schizophrenia, biological function studies of EGR3 in schizophrenia, the molecular regulatory mechanism of EGR3 and schizophrenia susceptibility candidate genes, and possible role of EGR3 in the immune system function in schizophrenia. In summary, EGR3 is a schizophrenia risk candidate factor and has comprehensive regulatory roles in schizophrenia pathogenesis. Further studies investigating the molecular mechanisms of EGR3 in schizophrenia are warranted for understanding the pathophysiology of this disorder as well as the development of new therapeutic strategies for the treatment and control of this disorder.
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Affiliation(s)
- Qi He
- School of Basic Medicine, Shaanxi Key Laboratory of Acupuncture and Medicine, Shannxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Ruochun Li
- Department of Medical Technology, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China
| | - Nannan Zhong
- Department of Medical Technology, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China
| | - Jie Ma
- Department of Electron Microscope, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Fayi Nie
- School of Basic Medicine, Shaanxi Key Laboratory of Acupuncture and Medicine, Shannxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Rui Zhang
- Department of Medical Technology, Guiyang Healthcare Vocational University, Guiyang, Guizhou, China
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Lv Y, Wen L, Hu WJ, Deng C, Ren HW, Bao YN, Su BW, Gao P, Man ZY, Luo YY, Li CJ, Xiang ZX, Wang B, Luan ZL. Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes. Metab Brain Dis 2024; 39:147-171. [PMID: 37542622 DOI: 10.1007/s11011-023-01271-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/27/2023] [Indexed: 08/07/2023]
Abstract
Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.
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Affiliation(s)
- Ye Lv
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Lin Wen
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Wen-Juan Hu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Chong Deng
- Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027, China
| | - Hui-Wen Ren
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ya-Nan Bao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Bo-Wei Su
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ping Gao
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Zi-Yue Man
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Yi-Yang Luo
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Cheng-Jie Li
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Zhi-Xin Xiang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Bing Wang
- Department of Endocrinology and Metabolism, The Central hospital of Dalian University of Technology, Dalian, 116000, China.
| | - Zhi-Lin Luan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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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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Su Y, Yang X, Yang L, Liu X, She Z, Zhang Y, Dong Z. Thyroid hormones regulate reelin expression in neuropsychiatric disorders. Can J Physiol Pharmacol 2022; 100:1033-1044. [PMID: 36166833 DOI: 10.1139/cjpp-2022-0270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The incidence and prevalence of hypothyroidism in pregnancy have increased over the past two decades, leading to the occurrence of neuropsychiatric disorders. However, the underlying mechanisms of thyroid hormone (TH)-regulated gene expression and neuropsychiatric development during the postnatal period remain unknown. Recent achievements have shown that reelin, a large extracellular glycoprotein, plays a crucial role in neuronal migration and localization during the development of neocortex and cerebellar cortex, thereby participating in the development of neuropsychiatric diseases. Reelin-induced neuronal migration requires triiodothyronine (T3) from the deiodination of thyroxine (T4) by fetal brain deiodinases. Previous studies have reported decreased reelin levels and abnormal gene expression, which are the same as the pathological alternations in reelin-induced neuropsychiatric disorders including schizophrenia and autism. Low T3 in the fetal brain due to hypothyroxinemia during pregnancy may be detrimental to neuronal migration, leading to neuropsychiatric disorders. In this review, we focus on the reelin expression between hypothyroidism and neuropsychiatric disorders.
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Affiliation(s)
- Yadi Su
- College of Stomatology, Chongqing Medical University, Chongqing, 401334, PR China
| | - Xiaoyu Yang
- College of Pediatrics, Chongqing Medical University, Chongqing, 401334, PR China
| | - Lu Yang
- College of Stomatology, Chongqing Medical University, Chongqing, 401334, PR China
| | - Xinjing Liu
- College of Public Health and Management, Chongqing Medical University, Chongqing, 401334, PR China
| | - Zhenghang She
- College of Pediatrics, Chongqing Medical University, Chongqing, 401334, PR China
| | - Youwen Zhang
- College of Pediatrics, Chongqing Medical University, Chongqing, 401334, PR China
| | - Zhifang Dong
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China
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Di Donato N, Guerrini R, Billington CJ, Barkovich AJ, Dinkel P, Freri E, Heide M, Gershon ES, Gertler TS, Hopkin RJ, Jacob S, Keedy SK, Kooshavar D, Lockhart PJ, Lohmann DR, Mahmoud IG, Parrini E, Schrock E, Severi G, Timms AE, Webster RI, Willis MJH, Zaki MS, Gleeson JG, Leventer RJ, Dobyns WB. Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders. Brain 2022; 145:3274-3287. [PMID: 35769015 PMCID: PMC9989350 DOI: 10.1093/brain/awac164] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/02/2022] [Accepted: 04/19/2022] [Indexed: 11/14/2022] Open
Abstract
Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.
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Affiliation(s)
- Nataliya Di Donato
- Institute for Clinical Genetics, University Hospital, TU Dresden, 01307 Dresden, Germany
| | - Renzo Guerrini
- Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50139 Florence, Italy
| | - Charles J Billington
- Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN 55454, USA
| | - A James Barkovich
- Departments of Radiology and Biomedical Imaging, Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Philine Dinkel
- Institute for Clinical Genetics, University Hospital, TU Dresden, 01307 Dresden, Germany
| | - Elena Freri
- Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Michael Heide
- Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
- German Primate Center, Leibniz Institute for Primate Research, 37077 Goettingen, Germany
| | - Elliot S Gershon
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
- Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA
| | - Tracy S Gertler
- Division of Neurology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
| | - Robert J Hopkin
- Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Department of Pediatrics, Division of Human Genetics, Cincinnati, OH 45229, USA
| | - Suma Jacob
- Department of Psychiatry, University of Minnesota, Minneapolis, MN 55454, USA
| | - Sarah K Keedy
- Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA
| | - Daniz Kooshavar
- Bruce Lefory Centre, Murdoch Children's Research Institute and University of Melbourne Department of Pediatrics, Melbourne 3052, Australia
| | - Paul J Lockhart
- Bruce Lefory Centre, Murdoch Children's Research Institute and University of Melbourne Department of Pediatrics, Melbourne 3052, Australia
| | - Dietmar R Lohmann
- Institut fur Humangenetik, Universitatsklinikum Essen, 45147 Essen, Germany
| | - Iman G Mahmoud
- Pediatric Neurology Department, Cairo University Children's Hospital, Cairo, Egypt
| | - Elena Parrini
- Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50139 Florence, Italy
| | - Evelin Schrock
- Institute for Clinical Genetics, University Hospital, TU Dresden, 01307 Dresden, Germany
| | - Giulia Severi
- Medical Genetics Unit, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy
| | - Andrew E Timms
- Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Richard I Webster
- T. Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney 2145, Australia
| | - Mary J H Willis
- Uniformed Services University School of Medicine and Naval Medical Center, Department of Pediatrics, San Diego, CA 92134, USA
| | - Maha S Zaki
- Pediatric Neurology Department, Cairo University Children's Hospital, Cairo, Egypt
- Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo Governorate 12622, Egypt
| | - Joseph G Gleeson
- Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA
| | - Richard J Leventer
- Department of Neurology, Royal Children's Hospital, Murdoch Children's Research Institute and University of Melbourne Department of Pediatrics, Melbourne 3052, Australia
| | - William B Dobyns
- Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN 55454, USA
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Yamaguchi R, Matsudaira I, Takeuchi H, Imanishi T, Kimura R, Tomita H, Kawashima R, Taki Y. RELN rs7341475 associates with brain structure in japanese healthy females. Neuroscience 2022; 494:38-50. [DOI: 10.1016/j.neuroscience.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 04/06/2022] [Accepted: 05/06/2022] [Indexed: 11/25/2022]
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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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Sánchez-Hidalgo AC, Martín-Cuevas C, Crespo-Facorro B, Garrido-Torres N. Reelin Alterations, Behavioral Phenotypes, and Brain Anomalies in Schizophrenia: A Systematic Review of Insights From Rodent Models. Front Neuroanat 2022; 16:844737. [PMID: 35401125 PMCID: PMC8986979 DOI: 10.3389/fnana.2022.844737] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/14/2022] [Indexed: 12/09/2022] Open
Abstract
Reelin is an extracellular matrix glycoprotein reduced in brain regions (the prefrontal cortex and the hippocampus) of patients with schizophrenia. There are diverse rodent models of schizophrenia that mimic patient symptoms based on various causal theories; however, likely shared reelin alterations have not yet been systematically assessed in those models. A systematic review of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model. Articles focused on psychotic disorders or schizophrenia and their relationship with reelin in rodent models were selected. Data (first author, publication year, results, both open field and prepulse inhibition test results, and type of reelin alteration) were extracted in duplicate by two independent reviewers. The 37 reviewed articles reported about various schizophrenia models and their reelin alterations, brain morphology, and behavioral defects. We conclude that reelin is an altered preclinical biomarker common to all models included, mainly prenatal or genetic models, and a key protein in schizophrenia disease, making the reelin signaling pathway in prenatal stages a target of special interest for future preclinical and clinical studies. All models presented at least one of the four described reelin alteration types. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021210568], identifier [CRD42021210568].
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Affiliation(s)
- Ana C. Sánchez-Hidalgo
- Spanish Network for Research in Mental Health (CIBERSAM), Madrid, Spain
- Seville Biomedical Research Centre (IBiS), Seville, Spain
| | - Celia Martín-Cuevas
- Spanish Network for Research in Mental Health (CIBERSAM), Madrid, Spain
- Seville Biomedical Research Centre (IBiS), Seville, Spain
| | - Benedicto Crespo-Facorro
- Spanish Network for Research in Mental Health (CIBERSAM), Madrid, Spain
- Seville Biomedical Research Centre (IBiS), Seville, Spain
- Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocío-IBiS, Seville, Spain
- *Correspondence: Benedicto Crespo-Facorro,
| | - Nathalia Garrido-Torres
- Spanish Network for Research in Mental Health (CIBERSAM), Madrid, Spain
- Seville Biomedical Research Centre (IBiS), Seville, Spain
- Department of Psychiatry, School of Medicine, University Hospital Virgen del Rocío-IBiS, Seville, Spain
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New Strategies for the Treatment of Neuropsychiatric Disorders Based on Reelin Dysfunction. Int J Mol Sci 2022; 23:ijms23031829. [PMID: 35163751 PMCID: PMC8836358 DOI: 10.3390/ijms23031829] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/31/2022] [Accepted: 02/03/2022] [Indexed: 12/16/2022] Open
Abstract
Reelin is an extracellular matrix protein that is mainly produced in Cajal-Retzius cells and controls neuronal migration, which is important for the proper formation of cortical layers in the developmental stage of the brain. In the adult brain, Reelin plays a crucial role in the regulation of N-methyl-D-aspartate receptor-dependent synaptic function, and its expression decreases postnatally. Clinical studies showed reductions in Reelin protein and mRNA expression levels in patients with psychiatric disorders; however, the causal relationship remains unclear. Reelin-deficient mice exhibit an abnormal neuronal morphology and behavior, while Reelin supplementation ameliorates learning deficits, synaptic dysfunctions, and spine loss in animal models with Reelin deficiency. These findings suggest that the neuronal deficits and brain dysfunctions associated with the down-regulated expression of Reelin are attenuated by enhancements in its expression and functions in the brain. In this review, we summarize findings on the role of Reelin in neuropsychiatric disorders and discuss potential therapeutic approaches for neuropsychiatric disorders associated with Reelin dysfunctions.
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