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1
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Martinez B, Peplow PV. Autism spectrum disorder: difficulties in diagnosis and microRNA biomarkers. Neural Regen Res 2025; 20:2776-2786. [PMID: 39314171 PMCID: PMC11826456 DOI: 10.4103/nrr.nrr-d-24-00712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/17/2024] [Accepted: 09/05/2024] [Indexed: 09/25/2024] Open
Abstract
We performed a PubMed search for microRNAs in autism spectrum disorder that could serve as diagnostic biomarkers in patients and selected 17 articles published from January 2008 to December 2023, of which 4 studies were performed with whole blood, 4 with blood plasma, 5 with blood serum, 1 with serum neural cell adhesion molecule L1-captured extracellular vesicles, 1 with blood cells, and 2 with peripheral blood mononuclear cells. Most of the studies involved children and the study cohorts were largely males. Many of the studies had performed microRNA sequencing or quantitative polymerase chain reaction assays to measure microRNA expression. Only five studies had used real-time polymerase chain reaction assay to validate microRNA expression in autism spectrum disorder subjects compared to controls. The microRNAs that were validated in these studies may be considered as potential candidate biomarkers for autism spectrum disorder and include miR-500a-5p, -197-5p, -424-5p, -664a-3p, -365a-3p, -619-5p, -664a-3p, -3135a, -328-3p, and -500a-5p in blood plasma and miR-151a-3p, -181b-5p, -320a, -328, -433, -489, -572, -663a, -101-3p, -106b-5p, -19b-3p, -195-5p, and -130a-3p in blood serum of children, and miR-15b-5p and -6126 in whole blood of adults. Several important limitations were identified in the studies reviewed, and need to be taken into account in future studies. Further studies are warranted with children and adults having different levels of autism spectrum disorder severity and consideration should be given to using animal models of autism spectrum disorder to investigate the effects of suppressing or overexpressing specific microRNAs as a novel therapy.
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Affiliation(s)
- Bridget Martinez
- Department of Pharmacology, University of Nevada-Reno, Reno, NV, USA
- Department of Medicine, University of Nevada-Reno, Reno, NV, USA
| | - Philip V. Peplow
- Department of Anatomy, University of Otago, Dunedin, New Zealand
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2
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Yao TT, Chen L, Du Y, Jiang ZY, Cheng Y. MicroRNAs as Regulators, Biomarkers, and Therapeutic Targets in Autism Spectrum Disorder. Mol Neurobiol 2025; 62:5039-5056. [PMID: 39503812 DOI: 10.1007/s12035-024-04582-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 10/22/2024] [Indexed: 03/05/2025]
Abstract
The pathogenesis of autism spectrum disorder (ASD) is complex and is mainly influenced by genetic and environmental factors. Some research has indicated that environmental aspects may interplay with genetic aspects to enhance the risk, and microRNAs (miRNAs) are probably factors in explaining this link between heredity and the environment. MiRNAs are single-stranded noncoding RNAs that can regulate gene expression at the posttranscriptional level. Some research has indicated that miRNAs are closely linked to neurological diseases. Many aberrantly expressed miRNAs have been observed in autism, and these dysregulated miRNAs are expected to be potential biomarkers and provide new strategies for the treatment of this disease. This article reviews the research progress of miRNAs in autism, including their biosynthesis and function. It is found that some miRNAs show aberrant expression patterns in brain tissue and peripheral blood of autistic patients, which may serve as biomarkers of the disease. In addition, the article explores the novel role of exosomes as carriers of miRNAs with the ability to cross the blood-brain barrier and unique expression profiles, offering new possibilities for diagnostic and therapeutic interventions in ASD. The potential of miRNAs in exosomes as diagnostic markers for ASD is specifically highlighted, as well as the prospect of using engineered exosome-encapsulated miRNAs for targeted therapies.
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Affiliation(s)
- Tong-Tong Yao
- Center On Translational Neuroscience, Institute of National Security, Minzu University of China, 27th South Zhongguancun Avenue, Beijing, 100081, China
- School of Ethnology and Sociology, Minzu University of China, Beijing, China
| | - Lei Chen
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Yang Du
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Zhong-Yong Jiang
- Department of Medical Laboratory, Affiliated Cancer Hospital of Chengdu Medical College, Chengdu Seventh People's Hospital, Chengdu, China.
| | - Yong Cheng
- Center On Translational Neuroscience, Institute of National Security, Minzu University of China, 27th South Zhongguancun Avenue, Beijing, 100081, China.
- Center On Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
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Stancioiu FA, Bogdan R, Ivanescu B, Dumitrescu R. Autologous cord blood vs individualized supplements in autistic spectrum disorder: CORDUS study results. World J Clin Pediatr 2025; 14:96643. [DOI: 10.5409/wjcp.v14.i1.96643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 10/03/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an equally ample effort to employ clinical studies for studying the ASD causes and cell therapies. Stem cells have yielded so far mixed results in clinical trials, and at patient level the results varied from impressive to no improvement. In this context we have administered autologous cord blood (ACB) and a non-placebo, material intervention represented by an individualized combination of supplements (ICS) to ASD children.
AIM To compare the efficacy of ACB vs ICS and find markers correlated with the child's progress in order to better predict ACB efficacy.
METHODS CORDUS clinical study is a crossover study in which both oral ICS and intravenous ACB were sequentially administered to 56 children; ACB was infused as an inpatient procedure. Treatment efficacy was evaluated pre-treatment and post-treatment at 6 months by an independent psychotherapist with Autism Treatment Evaluation Checklist, Quantitative Checklist for Autism in Toddlers and a 16-item comparative table score, after interviewing the children’s parents and therapists. Before and after each intervention participants had a set of blood tests including inflammatory, metabolic and oxidative markers, and the neuronal specific enolase.
RESULTS No serious adverse reactions were noted during and after cord blood or supplement administration. ACB improved evaluation scores in 78% of children with age 3–7-years (n = 28), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n = 28; only 11% of children improved scores). ICS yielded better results than ACB in 5 cases out of 28, while in 23 kids ACB brought more improvement than ICS (P < 0.05); high initial levels of inflammation and ferritin were associated with no improvement. Ample individual differences were noted in children's progress, and statistically significant improvements were seen after ACB on areas such as verbalization and social interaction, but not on irritability or aggressive behavior.
CONCLUSION ACB has superior efficacy to ICS in ASD; high inflammation, ferritin, age and body weight predict less improvement; more clinical studies are needed for studying ACB efficacy in ASD.
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Affiliation(s)
- Felician A Stancioiu
- Department of Clinical Research, Bio-Forum Foundation, Bucharest 040245, Bucuresti, Romania
| | - Raluca Bogdan
- Department of Pediatrics, Medicover Hospital Bucharest, Bucharest 013982, Bucuresti, Romania
| | | | - Radu Dumitrescu
- Department of Anesthesiology and Intensive Therapy, Medicover Hospital, Bucharest 013982, Bucuresti, Romania
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Mirabella F, Randazzo M, Rinaldi A, Pettinato F, Rizzo R, Sturiale L, Barone R. Glycosylation Pathways Targeted by Deregulated miRNAs in Autism Spectrum Disorder. Int J Mol Sci 2025; 26:783. [PMID: 39859496 PMCID: PMC11766332 DOI: 10.3390/ijms26020783] [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: 11/26/2024] [Revised: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Autism Spectrum Disorder (ASD) is a complex condition with a multifactorial aetiology including both genetic and epigenetic factors. MicroRNAs (miRNAs) play a role in ASD and may influence metabolic pathways. Glycosylation (the glycoconjugate synthesis pathway) is a necessary process for the optimal development of the central nervous system (CNS). Congenital Disorders of Glycosylation (CDGs) (CDGs) are linked to over 180 genes and are predominantly associated with neurodevelopmental disorders (NDDs) including ASD. From a literature search, we considered 64 miRNAs consistently deregulated in ASD patients (ASD-miRNAs). Computational tools, including DIANA-miRPath v3.0 and TarBase v8, were employed to investigate the potential involvement of ASD-miRNAs in glycosylation pathways. A regulatory network constructed through miRNet 2.0 revealed the involvement of these miRNAs in targeting genes linked to glycosylation. Protein functions were further validated through the Human Protein Atlas. A total of twenty-five ASD-miRNAs were identified, including nine miRNAs that were differentially expressed in cells or brain tissue in ASD patients and associated with glycosylation pathways, specifically protein N- and O-glycosylation and glycosaminoglycan biosynthesis (heparan sulfate). A number of CDG genes and/or ASD-risk genes, including DOLK, GALNT2, and EXT1, were identified as targets, along with validated interactions involving four key miRNAs (hsa-miR-423-5p, hsa-miR-30c-5p, hsa-miR-195-5p, and hsa-miR-132-5p). B4GALT1, an ASD susceptibility gene, emerged as a central regulatory hub, reinforcing the link between glycosylation and ASD. In sum, the evidence presented here supports the hypothesis that ASD-miRNAs mediate the epigenetic regulation of glycosylation, thus unveiling possible novel patho-mechanisms underlying ASD.
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Affiliation(s)
- Federica Mirabella
- Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy; (F.M.); (M.R.); (A.R.); (F.P.); (R.R.)
| | - Martina Randazzo
- Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy; (F.M.); (M.R.); (A.R.); (F.P.); (R.R.)
| | - Alessandro Rinaldi
- Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy; (F.M.); (M.R.); (A.R.); (F.P.); (R.R.)
| | - Fabio Pettinato
- Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy; (F.M.); (M.R.); (A.R.); (F.P.); (R.R.)
| | - Renata Rizzo
- Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy; (F.M.); (M.R.); (A.R.); (F.P.); (R.R.)
| | - Luisa Sturiale
- CNR—Institute for Polymers, Composites and Biomaterials IPCB, 95126 Catania, Italy;
| | - Rita Barone
- Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy; (F.M.); (M.R.); (A.R.); (F.P.); (R.R.)
- Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute—IRCCS, 94018 Troina, Italy
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Garrido-Torres N, Guzmán-Torres K, García-Cerro S, Pinilla Bermúdez G, Cruz-Baquero C, Ochoa H, García-González D, Canal-Rivero M, Crespo-Facorro B, Ruiz-Veguilla M. miRNAs as biomarkers of autism spectrum disorder: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2024; 33:2957-2990. [PMID: 36735095 PMCID: PMC11424746 DOI: 10.1007/s00787-023-02138-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/05/2023] [Indexed: 02/04/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex clinical manifestations that arise between 18 and 36 months of age. Social interaction deficiencies, a restricted range of interests, and repetitive stereotyped behaviors are characteristics which are sometimes difficult to detect early. Several studies show that microRNAs (miRs/miRNAs) are strongly implicated in the development of the disorder and affect the expression of genes related to different neurological pathways involved in ASD. The present systematic review and meta-analysis addresses the current status of miRNA studies in different body fluids and the most frequently dysregulated miRNAs in patients with ASD. We used a combined approach to summarize miRNA fold changes in different studies using the mean values. In addition, we summarized p values for differential miRNA expression using the Fisher method. Our literature search yielded a total of 133 relevant articles, 27 of which were selected for qualitative analysis based on the inclusion and exclusion criteria, and 16 studies evaluating miRNAs whose data were completely reported were ultimately included in the meta-analysis. The most frequently dysregulated miRNAs across the analyzed studies were miR-451a, miR-144-3p, miR-23b, miR-106b, miR150-5p, miR320a, miR92a-2-5p, and miR486-3p. Among the most dysregulated miRNAs in individuals with ASD, miR-451a is the most relevant to clinical practice and is associated with impaired social interaction. Other miRNAs, including miR19a-3p, miR-494, miR-142-3p, miR-3687, and miR-27a-3p, are differentially expressed in various tissues and body fluids of patients with ASD. Therefore, all these miRNAs can be considered candidates for ASD biomarkers. Saliva may be the optimal biological fluid for miRNA measurements, because it is easy to collect from children compared to other biological fluids.
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Affiliation(s)
- Nathalia Garrido-Torres
- Hospital Universitario Virgen Del Rocio, IBIS-CSIC, Department of Psychiatry, University of Sevilla, Avda Manuel Siurot S/N, 41013, Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Seville, Spain
| | | | - Susana García-Cerro
- Hospital Universitario Virgen Del Rocio, IBIS-CSIC, Department of Psychiatry, University of Sevilla, Avda Manuel Siurot S/N, 41013, Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Seville, Spain
| | | | | | - Hansel Ochoa
- Epidemiology Research Group (EpiAndes), Los Andes University, Bogotá, Colombia
| | - Diego García-González
- Hospital Universitario Virgen Del Rocio, IBIS-CSIC, Department of Psychiatry, University of Sevilla, Avda Manuel Siurot S/N, 41013, Seville, Spain
| | - Manuel Canal-Rivero
- Hospital Universitario Virgen Del Rocio, IBIS-CSIC, Department of Psychiatry, University of Sevilla, Avda Manuel Siurot S/N, 41013, Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Seville, Spain
| | - Benedicto Crespo-Facorro
- Hospital Universitario Virgen Del Rocio, IBIS-CSIC, Department of Psychiatry, University of Sevilla, Avda Manuel Siurot S/N, 41013, Seville, Spain.
- Spanish Network for Research in Mental Health (CIBERSAM), Seville, Spain.
| | - Miguel Ruiz-Veguilla
- Hospital Universitario Virgen Del Rocio, IBIS-CSIC, Department of Psychiatry, University of Sevilla, Avda Manuel Siurot S/N, 41013, Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Seville, Spain
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6
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García-Cerro S, Gómez-Garrido A, Garcia G, Crespo-Facorro B, Brites D. Exploratory Analysis of MicroRNA Alterations in a Neurodevelopmental Mouse Model for Autism Spectrum Disorder and Schizophrenia. Int J Mol Sci 2024; 25:2786. [PMID: 38474035 DOI: 10.3390/ijms25052786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/22/2024] [Accepted: 02/25/2024] [Indexed: 03/14/2024] Open
Abstract
MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.
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Affiliation(s)
- Susana García-Cerro
- Translational Psychiatry Group, Ibis-Biomedicine Institute of Sevilla-CSIC, Manuel Siurot AV, 41013 Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Monforte de Lemos AV, 3-5, 28029 Madrid, Spain
| | - Ana Gómez-Garrido
- Translational Psychiatry Group, Ibis-Biomedicine Institute of Sevilla-CSIC, Manuel Siurot AV, 41013 Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Monforte de Lemos AV, 3-5, 28029 Madrid, Spain
| | - Gonçalo Garcia
- Neuroinflammation, Signaling and Neuroregeneration Lab, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
- Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
| | - Benedicto Crespo-Facorro
- Translational Psychiatry Group, Ibis-Biomedicine Institute of Sevilla-CSIC, Manuel Siurot AV, 41013 Seville, Spain
- Spanish Network for Research in Mental Health (CIBERSAM), Monforte de Lemos AV, 3-5, 28029 Madrid, Spain
- Mental Health Unit, Virgen del Rocio University Hospital, Manuel Siurot AV, 41013 Seville, Spain
- Department of Psychiatry, Faculty of Medicine, University of Seville, Sánchez Pizjuán AV, 41013 Seville, Spain
| | - Dora Brites
- Neuroinflammation, Signaling and Neuroregeneration Lab, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
- Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
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7
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Huschner F, Głowacka-Walas J, Mills JD, Klonowska K, Lasseter K, Asara JM, Moavero R, Hertzberg C, Weschke B, Riney K, Feucht M, Scholl T, Krsek P, Nabbout R, Jansen AC, Petrák B, van Scheppingen J, Zamecnik J, Iyer A, Anink JJ, Mühlebner A, Mijnsbergen C, Lagae L, Curatolo P, Borkowska J, Sadowski K, Domańska-Pakieła D, Blazejczyk M, Jansen FE, Janson S, Urbanska M, Tempes A, Janssen B, Sijko K, Wojdan K, Jozwiak S, Kotulska K, Lehmann K, Aronica E, Jaworski J, Kwiatkowski DJ. Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years. Nat Commun 2023; 14:7664. [PMID: 37996417 PMCID: PMC10667269 DOI: 10.1038/s41467-023-42855-6] [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: 02/23/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.
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Affiliation(s)
| | - Jagoda Głowacka-Walas
- Transition Technologies Science, Warsaw, Poland
- Warsaw University of Technology, The Institute of Computer Science, Warsaw, Poland
| | - James D Mills
- Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK
- Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | | | - Kathryn Lasseter
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - John M Asara
- Department of Medicine, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Romina Moavero
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy
- Developmental Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Christoph Hertzberg
- Diagnose- und Behandlungszentrum für Kinder, Vivantes-Klinikum Neukölln, Berlin, Germany
| | - Bernhard Weschke
- Department of Child Neurology, Charité University Medicine Berlin, Berlin, Germany
| | - Kate Riney
- Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Queensland, Australia
- School of Medicine, University of Queensland, St Lucia, Queensland, Australia
| | - Martha Feucht
- Epilepsy Service, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Member of ERN EpiCARE, Vienna, Austria
| | - Theresa Scholl
- Epilepsy Service, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Member of ERN EpiCARE, Vienna, Austria
| | - Pavel Krsek
- Department of Paediatric Neurology, Motol University Hospital, 2nd Medical Faculty, Charles University, Prague, Czech Republic
| | - Rima Nabbout
- Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, Université Paris cité, Imagine Institute, Paris, France
| | - Anna C Jansen
- Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bořivoj Petrák
- Department of Paediatric Neurology, Motol University Hospital, 2nd Medical Faculty, Charles University, Prague, Czech Republic
| | - Jackelien van Scheppingen
- Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Josef Zamecnik
- Department. of Pathology and Molecular Medicine, Motol University Hospital, 2nd Medical Faculty, Charles University, Prague, Czech Republic
| | - Anand Iyer
- Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands
| | - Jasper J Anink
- Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Angelika Mühlebner
- Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Caroline Mijnsbergen
- Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands
| | - Lieven Lagae
- Department of Development and Regeneration Section Pediatric Neurology, University Hospitals KU Leuven, Leuven, Belgium
| | - Paolo Curatolo
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy
| | - Julita Borkowska
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
| | - Krzysztof Sadowski
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dorota Domańska-Pakieła
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
| | - Magdalena Blazejczyk
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
| | - Floor E Jansen
- Department of Child Neurology, Brain Center University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Malgorzata Urbanska
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
| | - Aleksandra Tempes
- International Institute of Molecular and Cell Biology, Warsaw, Poland
| | | | - Kamil Sijko
- Transition Technologies Science, Warsaw, Poland
| | - Konrad Wojdan
- Transition Technologies Science, Warsaw, Poland
- Warsaw University of Technology, Institute of Heat Engineering, Warsaw, Poland
| | - Sergiusz Jozwiak
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
- Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Kotulska
- Department of Neurology and Epileptology, member of ERN EPICARE, The Children's Memorial Health Institute, Warsaw, Poland
| | | | - Eleonora Aronica
- Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam, The Netherlands
- Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede the Netherlands, Utrecht, The Netherlands
| | - Jacek Jaworski
- International Institute of Molecular and Cell Biology, Warsaw, Poland
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8
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Guiducci L, Cabiati M, Santocchi E, Prosperi M, Morales MA, Muratori F, Randazzo E, Federico G, Calderoni S, Del Ry S. Expression of miRNAs in Pre-Schoolers with Autism Spectrum Disorders Compared with Typically Developing Peers and Its Effects after Probiotic Supplementation. J Clin Med 2023; 12:7162. [PMID: 38002774 PMCID: PMC10672692 DOI: 10.3390/jcm12227162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Alteration of the microbiota-gut-brain axis has been recently recognized as a possible contributor to the physiopathology of autism spectrum disorder (ASD). In this context, microRNA (miRNAs) dysfunction, implicated both in several neuropathological conditions including ASD and in different gastrointestinal disorders (GIDs), could represent an important modulating factor. In this contextual framework, we studied the transcriptional profile of specific circulating miRNAs associated with both ASD (miR-197-5p, miR-424-5p, miR-500a-5p, miR-664a-5p) and GID (miR-21-5p, miR-320a-5p, miR-31-5p, miR-223-5p) in a group of pre-schoolers with ASD and in typically developing (TD) peers. In the ASD group, we also assessed the same miRNAs after a 6-month supplementation with probiotics and their correlation with plasma levels of zonulin and lactoferrin. At baseline, the expression of miRNAs involved in ASD were significantly reduced in ASD pre-schoolers vs. TD controls. Regarding the miRNAs involved in GID, the expression levels of miR-320-5p, miR-31-5p, and miR-223-5p were significantly higher in ASD than in TD subjects, whereas miR-21-5p showed significantly reduced expression in the ASD group vs. TD group. Supplementation with probiotics did not significantly change the expression of miRNAs in the ASD population. We found a significative negative correlation between zonulin and miR-197-5p and miR-21-5p at baseline, as well as between lactoferrin and miR-223-5p after 6 months of probiotic supplementation. Our study confirms the presence of an altered profile of the miRNAs investigated in ASD versus TD peers that was not modified by supplementation with probiotics.
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Affiliation(s)
- Letizia Guiducci
- CNR, Institute of Clinical Physiology, 56124 Pisa, Italy; (L.G.); (M.C.); (M.A.M.); (S.D.R.)
| | - Manuela Cabiati
- CNR, Institute of Clinical Physiology, 56124 Pisa, Italy; (L.G.); (M.C.); (M.A.M.); (S.D.R.)
| | - Elisa Santocchi
- UFSMIA Zona Valle del Serchio, Azienda USL Toscana Nord Ovest, 55032 Castelnuovo di Garfagnana, Italy;
| | - Margherita Prosperi
- UFSMIA Valdera-Alta Val di Cecina, Azienda USL Toscana Nord Ovest, 56128 Pisa, Italy;
| | - Maria Aurora Morales
- CNR, Institute of Clinical Physiology, 56124 Pisa, Italy; (L.G.); (M.C.); (M.A.M.); (S.D.R.)
| | - Filippo Muratori
- Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy;
| | - Emioli Randazzo
- Unit of Pediatric Endocrinology and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (E.R.); (G.F.)
| | - Giovanni Federico
- Unit of Pediatric Endocrinology and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (E.R.); (G.F.)
| | - Sara Calderoni
- Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy;
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Silvia Del Ry
- CNR, Institute of Clinical Physiology, 56124 Pisa, Italy; (L.G.); (M.C.); (M.A.M.); (S.D.R.)
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9
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Hickman AR, Selee B, Pauly R, Husain B, Hang Y, Feltus FA. Discovery of eQTL Alleles Associated with Autism Spectrum Disorder: A Case-Control Study. J Autism Dev Disord 2023; 53:3595-3612. [PMID: 35739433 PMCID: PMC10465380 DOI: 10.1007/s10803-022-05631-x] [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] [Accepted: 05/27/2022] [Indexed: 11/27/2022]
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by challenges in social communication as well as repetitive or restrictive behaviors. Many genetic associations with ASD have been identified, but most associations occur in a fraction of the ASD population. Here, we searched for eQTL-associated DNA variants with significantly different allele distributions between ASD-affected and control. Thirty significant DNA variants associated with 174 tissue-specific eQTLs from ASD individuals in the SPARK project were identified. Several significant variants fell within brain-specific regulatory regions or had been associated with a significant change in gene expression in the brain. These eQTLs are a new class of biomarkers that could control the myriad of brain and non-brain phenotypic traits seen in ASD-affected individuals.
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Affiliation(s)
- Allison R. Hickman
- Genetics and Biochemistry Department, Clemson University, Clemson, SC 29634 USA
| | - Bradley Selee
- Electrical and Computer Engineering Department, Clemson University, Clemson, SC 29634 USA
| | - Rini Pauly
- Biomedical Data Science & Informatics Program, Clemson University, Clemson, SC 29634 USA
| | - Benafsh Husain
- Biomedical Data Science & Informatics Program, Clemson University, Clemson, SC 29634 USA
| | - Yuqing Hang
- Genetics and Biochemistry Department, Clemson University, Clemson, SC 29634 USA
| | - Frank Alex Feltus
- Genetics and Biochemistry Department, Clemson University, Clemson, SC 29634 USA
- Electrical and Computer Engineering Department, Clemson University, Clemson, SC 29634 USA
- Center for Human Genetics, Clemson University, Greenwood, SC 29646 USA
- Biosystems Research Complex, 302C, 105 Collings St, Clemson, SC 29634 USA
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10
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Stancioiu F, Bogdan R, Dumitrescu R. Neuron-Specific Enolase (NSE) as a Biomarker for Autistic Spectrum Disease (ASD). Life (Basel) 2023; 13:1736. [PMID: 37629593 PMCID: PMC10455327 DOI: 10.3390/life13081736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Autistic spectrum disease (ASD) is an increasingly common diagnosis nowadays with a prevalence of 1-2% in most countries. Its complex causality-a combination of genetic, immune, metabolic, and environmental factors-is translated into pleiomorphic developmental disorders of various severity, which have two main aspects in common: repetitive, restrictive behaviors and difficulties in social interaction varying from awkward habits and verbalization to a complete lack of interest for the outside world. The wide variety of ASD causes also makes it very difficult to find a common denominator-a disease biomarker and medication-and currently, there is no commonly used diagnostic and therapeutic strategy besides clinical evaluation and psychotherapy. In the CORDUS clinical study, we have administered autologous cord blood to ASD kids who had little or no improvement after other treatments and searched for a biomarker which could help predict the degree of improvement in each patient. We have found that the neuron-specific enolase (NSE) was elevated above the normal clinical range (less than 16.3 ng/mL) in the vast majority of ASD kids tested in our study (40 of 41, or 97.5%). This finding opens up a new direction for diagnostic confirmation, dynamic evaluation, and therapeutic intervention for ASD kids.
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Affiliation(s)
| | - Raluca Bogdan
- Medicover Hospital Bucharest, 013982 Bucharest, Romania
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11
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Kurtulmuş A, Koçana CÇ, Toprak SF, Sözer S. The role of Extracellular Genomic Materials (EGMs) in psychiatric disorders. Transl Psychiatry 2023; 13:262. [PMID: 37464177 PMCID: PMC10354097 DOI: 10.1038/s41398-023-02549-5] [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: 10/04/2022] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/20/2023] Open
Abstract
Extracellular Genomic Materials (EGMs) are the nucleic acids secreted or released from all types of cells by endogenous or exogenous stimuli through varying mechanisms into the extracellular region and inevitably to all biological fluids. EGMs could be found as free, protein-bound, and/ or with vesicles. EGMs can potentially have immunophenotypic and/or genotypic characteristics of a cell of origin, travel to distant organs, and interact with the new microenvironment. To achieve all, EGMs might bi-directionally transit through varying membranes, including the blood-brain barrier. Such ability provides the transfer of any information related to the pathophysiological changes in psychiatric disorders in the brain to the other distant organ systems or vice versa. In this article, many aspects of EGMs have been elegantly reviewed, including their potential in diagnosis as biomarkers, application in treatment modalities, and functional effects in the pathophysiology of psychiatric disorders. The psychiatric disorders were studied under subgroups of Schizophrenia spectrum disorders, bipolar disorder, depressive disorders, and an autism spectrum disorders. EGMs provide a robust and promising tool in clinics for prognosis and diagnosis. The successful application of EGMs into treatment modalities might further provide encouraging outcomes for researchers and clinicians in psychiatric disorders.
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Affiliation(s)
- Ayşe Kurtulmuş
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Institute of Health Sciences, Istanbul University, Istanbul, Turkey
- Istanbul Göztepe Prof.Dr.Süleyman Yalçın City Hospital, Department of Psychiatry, Istanbul, Turkey
| | - Cemal Çağıl Koçana
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Institute of Health Sciences, Istanbul University, Istanbul, Turkey
| | - Selin Fulya Toprak
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Institute of Health Sciences, Istanbul University, Istanbul, Turkey
| | - Selçuk Sözer
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
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12
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Stott J, Wright T, Holmes J, Wilson J, Griffiths-Jones S, Foster D, Wright B. A systematic review of non-coding RNA genes with differential expression profiles associated with autism spectrum disorders. PLoS One 2023; 18:e0287131. [PMID: 37319303 PMCID: PMC10270643 DOI: 10.1371/journal.pone.0287131] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/30/2023] [Indexed: 06/17/2023] Open
Abstract
AIMS To identify differential expression of shorter non-coding RNA (ncRNA) genes associated with autism spectrum disorders (ASD). BACKGROUND ncRNA are functional molecules that derive from non-translated DNA sequence. The HUGO Gene Nomenclature Committee (HGNC) have approved ncRNA gene classes with alignment to the reference human genome. One subset is microRNA (miRNA), which are highly conserved, short RNA molecules that regulate gene expression by direct post-transcriptional repression of messenger RNA. Several miRNA genes are implicated in the development and regulation of the nervous system. Expression of miRNA genes in ASD cohorts have been examined by multiple research groups. Other shorter classes of ncRNA have been examined less. A comprehensive systematic review examining expression of shorter ncRNA gene classes in ASD is timely to inform the direction of research. METHODS We extracted data from studies examining ncRNA gene expression in ASD compared with non-ASD controls. We included studies on miRNA, piwi-interacting RNA (piRNA), small NF90 (ILF3) associated RNA (snaR), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), transfer RNA (tRNA), vault RNA (vtRNA) and Y RNA. The following electronic databases were searched: Cochrane Library, EMBASE, PubMed, Web of Science, PsycINFO, ERIC, AMED and CINAHL for papers published from January 2000 to May 2022. Studies were screened by two independent investigators with a third resolving discrepancies. Data was extracted from eligible papers. RESULTS Forty-eight eligible studies were included in our systematic review with the majority examining miRNA gene expression alone. Sixty-four miRNA genes had differential expression in ASD compared to controls as reported in two or more studies, but often in opposing directions. Four miRNA genes had differential expression in the same direction in the same tissue type in at least 3 separate studies. Increased expression was reported in miR-106b-5p, miR-155-5p and miR-146a-5p in blood, post-mortem brain, and across several tissue types, respectively. Decreased expression was reported in miR-328-3p in bloods samples. Seven studies examined differential expression from other classes of ncRNA, including piRNA, snRNA, snoRNA and Y RNA. No individual ncRNA genes were reported in more than one study. Six studies reported differentially expressed snoRNA genes in ASD. A meta-analysis was not possible because of inconsistent methodologies, disparate tissue types examined, and varying forms of data presented. CONCLUSION There is limited but promising evidence associating the expression of certain miRNA genes and ASD, although the studies are of variable methodological quality and the results are largely inconsistent. There is emerging evidence associating differential expression of snoRNA genes in ASD. It is not currently possible to say whether the reports of differential expression in ncRNA may relate to ASD aetiology, a response to shared environmental factors linked to ASD such as sleep and nutrition, other molecular functions, human diversity, or chance findings. To improve our understanding of any potential association, we recommend improved and standardised methodologies and reporting of raw data. Further high-quality research is required to shine a light on possible associations, which may yet yield important information.
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Affiliation(s)
- Jon Stott
- Child Oriented Mental Health Intervention Collaborative (COMIC), University of York in Collaboration with Leeds and York Partnership NHS Foundation Trust, York, United Kingdom
- Tees, Esk & Wear Valleys NHS Foundation Trust, Foss Park Hospital, York, United Kingdom
| | - Thomas Wright
- Manchester Centre for Genomic Medicine, Clinical Genetics Service, Saint Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Jannah Holmes
- Child Oriented Mental Health Intervention Collaborative (COMIC), University of York in Collaboration with Leeds and York Partnership NHS Foundation Trust, York, United Kingdom
- Hull York Medical School, University of York, Heslington, York, United Kingdom
| | - Julie Wilson
- Department of Mathematics, University of York, Heslington, York, United Kingdom
| | - Sam Griffiths-Jones
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Deborah Foster
- Tees, Esk & Wear Valleys NHS Foundation Trust, Foss Park Hospital, York, United Kingdom
| | - Barry Wright
- Child Oriented Mental Health Intervention Collaborative (COMIC), University of York in Collaboration with Leeds and York Partnership NHS Foundation Trust, York, United Kingdom
- Hull York Medical School, University of York, Heslington, York, United Kingdom
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13
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Brown JS. Comparison of Oncogenes, Tumor Suppressors, and MicroRNAs Between Schizophrenia and Glioma: The Balance of Power. Neurosci Biobehav Rev 2023; 151:105206. [PMID: 37178944 DOI: 10.1016/j.neubiorev.2023.105206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/25/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023]
Abstract
The risk of cancer in schizophrenia has been controversial. Confounders of the issue are cigarette smoking in schizophrenia, and antiproliferative effects of antipsychotic medications. The author has previously suggested comparison of a specific cancer like glioma to schizophrenia might help determine a more accurate relationship between cancer and schizophrenia. To accomplish this goal, the author performed three comparisons of data; the first a comparison of conventional tumor suppressors and oncogenes between schizophrenia and cancer including glioma. This comparison determined schizophrenia has both tumor-suppressive and tumor-promoting characteristics. A second, larger comparison between brain-expressed microRNAs in schizophrenia with their expression in glioma was then performed. This identified a core carcinogenic group of miRNAs in schizophrenia offset by a larger group of tumor-suppressive miRNAs. This proposed "balance of power" between oncogenes and tumor suppressors could cause neuroinflammation. This was assessed by a third comparison between schizophrenia, glioma and inflammation in asbestos-related lung cancer and mesothelioma (ALRCM). This revealed that schizophrenia shares more oncogenic similarity to ALRCM than glioma.
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14
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Dominguez-Alonso S, Carracedo A, Rodriguez-Fontenla C. The non-coding genome in Autism Spectrum Disorders. Eur J Med Genet 2023; 66:104752. [PMID: 37023975 DOI: 10.1016/j.ejmg.2023.104752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 03/10/2023] [Accepted: 03/19/2023] [Indexed: 04/08/2023]
Abstract
Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders (NDDs) characterized by difficulties in social interaction and communication, repetitive behavior, and restricted interests. While ASD have been proven to have a strong genetic component, current research largely focuses on coding regions of the genome. However, non-coding DNA, which makes up for ∼99% of the human genome, has recently been recognized as an important contributor to the high heritability of ASD, and novel sequencing technologies have been a milestone in opening up new directions for the study of the gene regulatory networks embedded within the non-coding regions. Here, we summarize current progress on the contribution of non-coding alterations to the pathogenesis of ASD and provide an overview of existing methods allowing for the study of their functional relevance, discussing potential ways of unraveling ASD's "missing heritability".
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Affiliation(s)
- S Dominguez-Alonso
- Grupo de Medicina Xenómica, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain
| | - A Carracedo
- Grupo de Medicina Xenómica, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain
| | - C Rodriguez-Fontenla
- Grupo de Medicina Xenómica, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
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15
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Zhang Y, Pang Y, Feng W, Jin Y, Chen S, Ding S, Wang Z, Zou Y, Li Y, Wang T, Sun P, Gao J, Zhu Y, Ke X, Marshall C, Huang H, Sheng C, Xiao M. miR-124 regulates early isolation-induced social abnormalities via inhibiting myelinogenesis in the medial prefrontal cortex. Cell Mol Life Sci 2022; 79:507. [PMID: 36059036 PMCID: PMC11803008 DOI: 10.1007/s00018-022-04533-6] [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: 05/14/2022] [Revised: 08/18/2022] [Accepted: 08/18/2022] [Indexed: 01/10/2023]
Abstract
Patients with autism spectrum disorder (ASD) typically experience substantial social isolation, which may cause secondary adverse effects on their brain development. miR-124 is the most abundant miRNA in the human brain, acting as a pivotal molecule regulating neuronal fate determination. Alterations of miR-124 maturation or expression are observed in various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. In the present study, we analyzed a panel of brain-enriched microRNAs in serums from 2 to 6 year old boys diagnosed with ASD. The hsa-miR-124 level was found significantly elevated in ASD boys than in age and sex-matched healthy controls. In an isolation-reared weanling mouse model, we evidenced elevated mmu-miR-124 level in the serum and the medial prefrontal cortex (mPFC). These mice displayed significant sociability deficits, as well as myelin abnormality in the mPFC, which was partially rescued by expressing the miR-124 sponge in the bilateral mPFC, ubiquitously or specifically in oligodendroglia. In cultured mouse oligodendrocyte precursor cells, introducing a synthetic mmu-miR-124 inhibited the differentiation process through suppressing expression of nuclear receptor subfamily 4 group A member 1 (Nr4a1). Overexpressing Nr4a1 in the bilateral mPFC also corrected the social behavioral deficits and myelin impairments in the isolation-reared mice. This study revealed an unanticipated role of the miR-124/Nr4a1 signaling in regulating early social experience-dependent mPFC myelination, which may serve as a potential therapy target for social neglect or social isolation-related neuropsychiatric disorders.
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Affiliation(s)
- Yanli Zhang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Yingting Pang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Weixi Feng
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yuxi Jin
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Sijia Chen
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Shixin Ding
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Ze Wang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
| | - Ying Zou
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yun Li
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Tianqi Wang
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Peng Sun
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Junying Gao
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yi Zhu
- Department of Rehabilitation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaoyan Ke
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China
| | - Charles Marshall
- Department of Rehabilitation Sciences, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, USA
| | - Huang Huang
- Department of Neurology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China.
| | - Chengyu Sheng
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
| | - Ming Xiao
- Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
- Brain Institute, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, 210029, China.
- Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
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16
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Sun L, Wang X, Wang X, Cui X, Li G, Wang L, Wang L, Song M, Yu L. Genome-wide DNA methylation profiles of autism spectrum disorder. Psychiatr Genet 2022; 32:131-145. [PMID: 35353793 DOI: 10.1097/ypg.0000000000000314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES We aimed to identify differentially methylated genes and related signaling pathways in autism spectrum disorder (ASD). METHODS First, the DNA methylation profile in the brain samples (GSE131706 and GSE80017) and peripheral blood samples (GSE109905) was downloaded from the Gene Expression Omnibus database (GEO) dataset, followed by identification of differentially methylated genes and functional analysis. Second, the GSE109905 data set was used to further validate the methylation state and test the ability to diagnose disease of identified differentially methylated genes. Third, expression measurement of selected differentially methylated genes was performed in whole blood from an independent sample. Finally, protein-protein interaction (PPI) network of core differentially methylated genes was constructed. RESULTS Totally, 74 differentially methylated genes were identified in ASD, including 38 hypermethylated genes and 36 hypomethylated genes. 15 differentially methylated genes were further identified after validation in the GSE109905 data set. Among these, major histocompatibility complex (HLA)-DQA1 was involved in the molecular function of myosin heavy chain class II receptor activity; HLA-DRB5 was involved in the signaling pathways of cell adhesion molecules, Epstein-Barr virus infection and antigen processing and presentation. In the PPI analysis, the interaction pairs of HLA-DQA1 and HLA-DRB5, FMN2 and ACTR3, and CALCOCO2 and BAZ2B were identified. Interestingly, FMN2, BAZ2B, HLA-DRB5, CALCOCO2 and DUSP22 had a potential diagnostic value for patients with ASD. The expression result of four differentially methylated genes (HLA-DRB5, NTM, IL16 and COL5A3) in the independent sample was consistent with the integrated analysis. CONCLUSIONS Identified differentially methylated genes and enriched signaling pathway could be associated with ASD.
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Affiliation(s)
- Ling Sun
- Mental Health Center, The First Hospital of Hebei Medical University
- Medical Department
| | - Xueyi Wang
- Mental Health Center, The First Hospital of Hebei Medical University
| | - Xia Wang
- Child Health Department (Psychological Behavior Department)
| | | | | | - Le Wang
- Institute of Pediatric Research, Children's Hospital of Hebei Province, China
| | - Lan Wang
- Mental Health Center, The First Hospital of Hebei Medical University
| | - Mei Song
- Mental Health Center, The First Hospital of Hebei Medical University
| | - Lulu Yu
- Mental Health Center, The First Hospital of Hebei Medical University
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17
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Kynurenine pathway and autism spectrum phenotypes: an investigation among adults with autism spectrum disorder and their first-degree relatives. CNS Spectr 2022; 28:374-385. [PMID: 35634735 DOI: 10.1017/s1092852922000840] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Increasing literature highlighted alterations of tryptophan (TRP) metabolism and kynurenine (KYN) pathway in children with autism spectrum disorder (ASD). However, no study specifically focused on adult samples. Meanwhile, several authors stressed the relevance of investigating neurobiological correlates of adult forms of ASD and of those subthreshold ASD manifestations frequently found in relatives of ASD probands, known as broad autism phenotype (BAP). This work aimed to evaluate circulating levels of TRP and metabolites of KYN pathway in a sample of ASD adults, their first-degree relatives and controls (CTLs), investigating also the correlations between biochemical variables' levels and ASD symptoms. METHODS A sample of ASD adults, together with a group of first-degree relatives (BAP group) and unrelated CTLs were assessed by means of psychometric scales. Circulating levels of TRP, KYN, quinolinic acid (QA), and kynurenic acid (KYNA) were assessed in all subjects. RESULTS ASD patients reported significantly higher total scores than the other groups on all psychometric scales. BAP subjects scored significantly higher than CTLs. ASD patients reported significantly lower TRP levels than BAP and CTL groups. Moreover, significantly lower levels of KYNA were reported in both ASD and BAP groups than in CTLs. Specific patterns of associations were found between autism symptoms and biochemical variables. CONCLUSIONS Our findings confirm in adult samples the presence of altered TRP metabolism through KYN pathway. The intermediate alterations reported among relatives of ASD patients further stress the presence of a continuum between subthreshold and full-threshold ASD phenotypes also from a biochemical perspective.
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Identification of Peripheral Blood miRNA Biomarkers in First-Episode Drug-Free Schizophrenia Patients Using Bioinformatics Strategy. Mol Neurobiol 2022; 59:4730-4746. [DOI: 10.1007/s12035-022-02878-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 05/12/2022] [Indexed: 11/26/2022]
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Yang C, Kang B, Cao Z, Zhang J, Zhao F, Wang D, Su P, Chen J. Early-Life Pb Exposure Might Exert Synapse-Toxic Effects Via Inhibiting Synapse-Associated Membrane Protein 2 (VAMP2) Mediated by Upregulation of miR-34b. J Alzheimers Dis 2022; 87:619-633. [DOI: 10.3233/jad-215638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Early-life Pb exposure can cause behavioral and cognitive problems and induce symptoms of hyperactivity, impulsivity, and inattention in children. Studies showed that blood lead levels were highly correlated with neuropsychiatric disorders, and effects of neurotoxicity might persist and affect the incidence of neurodegenerative diseases, for example Alzheimer’s disease (AD). Objective: To explore possible mechanisms of developmental Pb-induced neuropsychiatric dysfunctions. Methods: Children were divided into low blood lead level (BLL) group (0–50.00μg/L) and high BLL group (> 50.00μg/L) and blood samples were collected. miRNA array was used to testify miRNA expression landscape between two groups. Correlation analysis and real-time PCR were applied to find miRNAs that altered in Pb and neuropsychiatric diseases. Animal models and cell experiments were used to confirm the effect of miRNAs in response to Pb, and siRNA and luciferase experiments were conducted to examine their effect on neural functions. Results: miRNA array data and correlation analysis showed that miR-34b was the most relevant miRNA among Pb neurotoxicity and neuropsychiatric disorders, and synapse-associated membrane protein 2 (VAMP2) was the target gene regulating synapse function. In vivo and in vitro studies showed Pb exposure injured rats’ cognitive abilities and induced upregulation of miR-34b and downregulation of VAMP2, resulting in decreases of hippocampal synaptic vesicles. Blockage of miR-34b mitigated Pb’s effects on VAMP2 in vitro. Conclusion: Early-life Pb exposure might exert synapse-toxic effects via inhibiting VAMP2 mediated by upregulation of miR-34b and shed a light on the underlying relationship between Pb neurotoxicity and developmental neuropsychiatric disorders.
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Affiliation(s)
- Changhao Yang
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Beipei Kang
- Department of Clinical Laboratory, Xijing Hospital, Air Force Military Medical University, Xi’an, China
| | - Zipeng Cao
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an, China
| | - Jianbin Zhang
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an, China
| | - Fang Zhao
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an, China
| | - Diya Wang
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an, China
| | - Peng Su
- Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an, China
| | - Jingyuan Chen
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
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20
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Gill PS, Clothier JL, Veerapandiyan A, Dweep H, Porter-Gill PA, Schaefer GB. Molecular Dysregulation in Autism Spectrum Disorder. J Pers Med 2021; 11:848. [PMID: 34575625 PMCID: PMC8466026 DOI: 10.3390/jpm11090848] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/21/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.
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Affiliation(s)
- Pritmohinder S. Gill
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA;
- Arkansas Children’s Research Institute, 13 Children’s Way, Little Rock, AR 72202, USA;
| | - Jeffery L. Clothier
- Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Aravindhan Veerapandiyan
- Pediatric Neurology, Arkansas Children’s Hospital, 1 Children’s Way, Little Rock, AR 72202, USA;
| | - Harsh Dweep
- The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA;
| | | | - G. Bradley Schaefer
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA;
- Genetics and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
- Arkansas Children’s Hospital NW, Springdale, AR 72762, USA
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21
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Kichukova T, Petrov V, Popov N, Minchev D, Naimov S, Minkov I, Vachev T. Identification of serum microRNA signatures associated with autism spectrum disorder as promising candidate biomarkers. Heliyon 2021; 7:e07462. [PMID: 34286132 PMCID: PMC8278430 DOI: 10.1016/j.heliyon.2021.e07462] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/06/2021] [Accepted: 06/29/2021] [Indexed: 01/15/2023] Open
Abstract
Background MicroRNAs (miRNAs) are short non-coding RNA molecules with a well-recognized role in gene expression mostly at the post-transcriptional level. Recently, dysregulation of miRNAs and miRNA-mRNA interactions has been associated with CNS diseases, including numerous psychiatric disorders. Dynamic changes in the expression profiles of circulating miRNA are nowadays regarded as promising non-invasive biomarkers that may facilitate the accurate and timely diagnosis of complex conditions. Methods In this study, we investigated the gene expression patterns of four miRNAs, which were previously reported to be dysregulated in pooled serum samples taken from Autism Spectrum Disorder (ASD) patients and typically developing children. The performance of a diagnostic model for ASD based on these four miRNAs was assessed by a receiver operating characteristic (ROC) curve analysis, which evaluates the diagnostic accuracy of the investigated miRNA biomarkers for ASD. Finally, to examine the potential modulation of CNS-related biological pathways, we carried out target identification and pathway analyses of the selected miRNAs. Results Significant differential expression for all the four studied miRNAs: miR-500a-5p, miR-197-5p, miR-424-5p, and miR-664a-3p, was consistently measured in the samples from ASD patients. The ROC curve analysis demonstrated high sensitivity and specificity for miR-500a-5p, miR-197-5p, and miR-424-5p. With all miRNA expression data integrated into an additive ROC curve, the combination of miR-500a-5p and miR-197-5p provided the most powerful diagnostic model. On the other hand, the mRNA target mining showed that miR-424-5p and miR-500-5p regulate pools of target mRNA molecules which are enriched in a number of biological pathways associated with the development and differentiation of the nervous system. Conclusions The steady expression patterns of miR-500a-5p, miR-197-5p, miR-424-5p, and miR-664a-3p in ASD children suggest that these miRNAs can be considered good candidates for non-invasive molecular biomarkers in the study of ASD patients. The highest diagnostic potential is manifested by miR-500a-5p and miR-197-5p, whose combined ROC curve demonstrates very strong predictive accuracy.
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Affiliation(s)
- Tatyana Kichukova
- Department of Plant Physiology and Molecular Biology, "Paisii Hilendarski" University of Plovdiv, 24 Tzar Assen Street, Plovdiv, Bulgaria
| | - Veselin Petrov
- Department of Plant Physiology, Biochemistry and Genetics, Agricultural University of Plovdiv, Bulgaria
| | - Nikolay Popov
- Psychiatric Ward for Active Treatment of Men, State Psychiatry Hospital Pazardzhik, Pazardzhik, Bulgaria
| | - Danail Minchev
- Department of Medical Biology, Faculty of Medicine, Medical University-Plovdiv, 15-A Vassil Aprilov Blvd., Plovdiv, Bulgaria.,Division of Molecular and Regenerative Medicine, Research Institute at Medical University of 12 Plovdiv, 15A Vasil Aprilov Blvd, Plovdiv, 4000, Bulgaria
| | - Samir Naimov
- Department of Plant Physiology and Molecular Biology, "Paisii Hilendarski" University of Plovdiv, 24 Tzar Assen Street, Plovdiv, Bulgaria
| | - Ivan Minkov
- Institute of Molecular Biology and Biotechnologies (IMBB), Plovdiv, Bulgaria
| | - Tihomir Vachev
- Department of Plant Physiology and Molecular Biology, "Paisii Hilendarski" University of Plovdiv, 24 Tzar Assen Street, Plovdiv, Bulgaria
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22
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Juvale IIA, Che Has AT. The Potential Role of miRNAs as Predictive Biomarkers in Neurodevelopmental Disorders. J Mol Neurosci 2021; 71:1338-1355. [PMID: 33774758 DOI: 10.1007/s12031-021-01825-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/02/2021] [Indexed: 12/22/2022]
Abstract
Neurodevelopmental disorders are defined as a set of abnormal brain developmental conditions marked by the early childhood onset of cognitive, behavioral, and functional deficits leading to memory and learning problems, emotional instability, and impulsivity. Autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, fragile X syndrome, and Down's syndrome are a few known examples of neurodevelopmental disorders. Although they are relatively common in both developed and developing countries, very little is currently known about their underlying molecular mechanisms. Both genetic and environmental factors are known to increase the risk of neurodevelopmental disorders. Current diagnostic and screening tests for neurodevelopmental disorders are not reliable; hence, individuals with neurodevelopmental disorders are often diagnosed in the later stages. This negatively affects their prognosis and quality of life, prompting the need for a better diagnostic biomarker. Recent studies on microRNAs and their altered regulation in diseases have shed some light on the possible role they could play in the development of the central nervous system. This review attempts to elucidate our current understanding of the role that microRNAs play in neurodevelopmental disorders with the hope of utilizing them as potential biomarkers in the future.
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Affiliation(s)
- Iman Imtiyaz Ahmed Juvale
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Ahmad Tarmizi Che Has
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.
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23
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Wang J, Yang Z, Chen C, Xu Y, Wang H, Liu B, Zhang W, Jiang Y. Comprehensive circRNA Expression Profile and Construction of circRNAs-Related ceRNA Network in a Mouse Model of Autism. Front Genet 2021; 11:623584. [PMID: 33679870 PMCID: PMC7928284 DOI: 10.3389/fgene.2020.623584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/23/2020] [Indexed: 12/27/2022] Open
Abstract
Autism is a common disease that seriously affects the quality of life. The role of circular RNAs (circRNAs) in autism remains largely unexplored. We aimed to detect the circRNA expression profile and construct a circRNA-based competing endogenous RNA (ceRNA) network in autism. Valproate acid was used to establish an in vivo model of autism in mice. A total of 1,059 differentially expressed circRNAs (477 upregulated and 582 downregulated) in autism group was identified by RNA sequencing. The expression of novel_circ_015779 and novel_circ_035247 were detected by real-time PCR. A ceRNA network based on altered circRNAs was established, with 9,715 nodes and 150,408 edges. Module analysis was conducted followed by GO and KEGG pathway enrichment analysis. The top three modules were all correlated with autism-related pathways involving “TGF-beta signaling pathway,” “Notch signaling pathway,” “MAPK signaling pathway,” “long term depression,” “thyroid hormone signaling pathway,” etc. The present study reveals a novel circRNA involved mechanisms in the pathogenesis of autism.
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Affiliation(s)
- Ji Wang
- Yangzhou Maternal and Child Health Hospital, Yangzhou, China.,Harbin Children's Hospital, Harbin, China
| | - Zhongxiu Yang
- Xuzhou Children's Hospital, Xuzhou Medical University, Xuzhou, China
| | - Canming Chen
- Yangzhou Maternal and Child Health Hospital, Yangzhou, China
| | - Yang Xu
- Yangzhou Maternal and Child Health Hospital, Yangzhou, China
| | - Hongguang Wang
- School of Civil Engineering, Northeast Forestry University, Harbin, China
| | - Bing Liu
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Wei Zhang
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yanan Jiang
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.,Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
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24
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Mirabella F, Gulisano M, Capelli M, Lauretta G, Cirnigliaro M, Palmucci S, Stella M, Barbagallo D, Di Pietro C, Purrello M, Ragusa M, Rizzo R. Enrichment and Correlation Analysis of Serum miRNAs in Comorbidity Between Arnold-Chiari and Tourette Syndrome Contribute to Clarify Their Molecular Bases. Front Mol Neurosci 2021; 13:608355. [PMID: 33469418 PMCID: PMC7813987 DOI: 10.3389/fnmol.2020.608355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 12/04/2020] [Indexed: 12/27/2022] Open
Abstract
Due to its rarity, coupled to a multifactorial and very heterogeneous nature, the molecular etiology of Arnold-Chiari (AC) syndrome remains almost totally unknown. Its relationship with other neuropsychiatric disorders such as Tourette syndrome (TS) is also undetermined. The rare comorbid status between both disorders (ACTS) complicates the framework of diagnosis and negatively affects the patients' quality of life. In this exploratory study, we aimed to identify serum microRNA expression profiles as molecular fingerprints for AC, TS, and ACTS, by using a high-throughput approach. For this aim, 10 AC patients, 11 ACTS patients, 6 TS patients, and 8 unaffected controls (NC) were recruited. Nine miRNAs resulted significantly differentially expressed (DE): let-7b-5p (upregulated in ACTS vs. TS); miR-21-5p (upregulated in ACTS vs. AC; downregulated in AC vs. TS); miR-23a-3p (upregulated in TS vs. NCs; downregulated in AC vs. TS); miR-25-3p (upregulated in AC vs. TS and NCs; downregulated in ACTS vs. AC); miR-93-5p (upregulated in AC vs. TS); miR-130a-3p (downregulated in ACTS and TS vs. NCs); miR-144-3p (downregulated in ACTS vs. AC; upregulated in AC vs. TS); miR-222-3p (upregulated in ACTS vs. NCs); miR-451a (upregulated in AC vs. TS and NCs; in ACTS vs. NCs). Altered expression of miRNAs was statistically correlated to neuroimaging and neuropsychological anomalies. Furthermore, computational analyses indicated that DE miRNAs are involved in AC and TS pathomechanisms. Finally, we propose the dysregulation of the miRNA set as a potential molecular tool for supporting the current diagnosis of AC, TS, and ACTS by using liquid biopsies, in an unbiased and non-invasive way.
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Affiliation(s)
- Federica Mirabella
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Mariangela Gulisano
- Section of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Mara Capelli
- Section of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Giovanni Lauretta
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Matilde Cirnigliaro
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Stefano Palmucci
- Radiology Unit 1, Department of Medical Surgical Sciences and Advanced Technologies, University Hospital “Policlinico-Vittorio Emanuele”, University of Catania, Catania, Italy
| | - Michele Stella
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Davide Barbagallo
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Cinzia Di Pietro
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Michele Purrello
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Marco Ragusa
- Section of Biology and Genetics Giovanni Sichel, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
- Oasi Research Institute–IRCCS, Troina, Italy
| | - Renata Rizzo
- Section of Child and Adolescent Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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25
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Huang ZX, Chen Y, Guo HR, Chen GF. Systematic Review and Bioinformatic Analysis of microRNA Expression in Autism Spectrum Disorder Identifies Pathways Associated With Cancer, Metabolism, Cell Signaling, and Cell Adhesion. Front Psychiatry 2021; 12:630876. [PMID: 34744804 PMCID: PMC8566729 DOI: 10.3389/fpsyt.2021.630876] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Previous studies have identified differentially expressed microRNAs in autism spectrum disorder (ASD), however, results are discrepant. We aimed to systematically review this topic and perform bioinformatic analysis to identify genes and pathways associated with ASD miRNAs. Methods: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses, we searched the Web of Science, PubMed, Embase, Scopus, and OVID databases to identify all studies comparing microRNA expressions between ASD persons and non-ASD controls on May 11, 2020. We obtained ASD miRNA targets validated by experimental assays from miRTarBase and performed pathway enrichment analysis using Metascape and DIANA-miRPath v3. 0. Results: Thirty-four studies were included in the systematic review. Among 285 altered miRNAs reported in these studies, 15 were consistently upregulated, 14 were consistently downregulated, and 39 were inconsistently dysregulated. The most frequently altered miRNAs including miR-23a-3p, miR-106b-5p, miR-146a-5p, miR-7-5p, miR-27a-3p, miR-181b-5p, miR-486-3p, and miR-451a. Subgroup analysis of tissues showed that miR-146a-5p, miR-155-5p, miR-1277-3p, miR-21-3p, miR-106b-5p, and miR-451a were consistently upregulated in brain tissues, while miR-4742-3p was consistently downregulated; miR-23b-3p, miR-483-5p, and miR-23a-3p were consistently upregulated in blood samples, while miR-15a-5p, miR-193a-5p, miR-20a-5p, miR-574-3p, miR-92a-3p, miR-3135a, and miR-103a-3p were consistently downregulated; miR-7-5p was consistently upregulated in saliva, miR-23a-3p and miR-32-5p were consistently downregulated. The altered ASD miRNAs identified in at least two independent studies were validated to target many autism risk genes. TNRC6B, PTEN, AGO1, SKI, and SMAD4 were the most frequent targets, and miR-92a-3p had the most target autism risk genes. Pathway enrichment analysis showed that ASD miRNAs are significantly involved in pathways associated with cancer, metabolism (notably Steroid biosynthesis, Fatty acid metabolism, Fatty acid biosynthesis, Lysine degradation, Biotin metabolism), cell cycle, cell signaling (especially Hippo, FoxO, TGF-beta, p53, Thyroid hormone, and Estrogen signaling pathway), adherens junction, extracellular matrix-receptor interaction, and Prion diseases. Conclusions: Altered miRNAs in ASD target autism risk genes and are involved in various ASD-related pathways, some of which are understudied and require further investigation.
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Affiliation(s)
- Zhi-Xiong Huang
- Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yanhui Chen
- Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hong-Ru Guo
- Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou, China
| | - Guo-Feng Chen
- Department of Pediatrics, Fujian Medical University Union Hospital, Fuzhou, China
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26
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Konečná B, Radošinská J, Keményová P, Repiská G. Detection of disease-associated microRNAs - application for autism spectrum disorders. Rev Neurosci 2020; 31:757-769. [PMID: 32813679 DOI: 10.1515/revneuro-2020-0015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022]
Abstract
Autism spectrum disorders (ASD) diagnostic procedure still lacks a uniform biological marker. This review gathers the information on microRNAs (miRNAs) specifically as a possible source of biomarkers of ASD. Extracellular vesicles, and their subset of exosomes, are believed to be a tool of cell-to-cell communication, and they are increasingly considered to be carriers of such a marker. The interest in studying miRNAs in extracellular vesicles grows in all fields of study and therefore should not be omitted in the field of neurodevelopmental disorders. The summary of miRNAs associated with brain cells and ASD either studied directly in the tissue or biofluids are gathered in this review. The heterogeneity in findings from different studies points out the fact that unified methods should be established, beginning with the determination of the accurate patient and control groups, through to sample collection, processing, and storage conditions. This review, based on the available literature, proposes the standardized approach to obtain the results that would not be affected by technical factors. Nowadays, the method of high-throughput sequencing seems to be the most optimal to analyze miRNAs. This should be followed by the uniformed bioinformatics procedure to avoid misvalidation. At the end, the proper validation of the obtained results is needed. With such an approach as is described in this review, it would be possible to obtain a reliable biomarker that would characterize the presence of ASD.
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Affiliation(s)
- Barbora Konečná
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia
| | - Jana Radošinská
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 813 72 Bratislava, Slovakia
- Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
| | - Petra Keményová
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 813 72 Bratislava, Slovakia
| | - Gabriela Repiská
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, 813 72 Bratislava, Slovakia
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27
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Wu X, Li W, Zheng Y. Recent Progress on Relevant microRNAs in Autism Spectrum Disorders. Int J Mol Sci 2020; 21:ijms21165904. [PMID: 32824515 PMCID: PMC7460584 DOI: 10.3390/ijms21165904] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 01/10/2023] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathogenesis is unclear and is affected by both genetic and environmental factors. The microRNAs (miRNAs) are a kind of single-stranded non-coding RNA with 20-22 nucleotides, which normally inhibit their target mRNAs at a post-transcriptional level. miRNAs are involved in almost all biological processes and are closely related to ASD and many other diseases. In this review, we summarize relevant miRNAs in ASD, and analyze dysregulated miRNAs in brain tissues and body fluids of ASD patients, which may contribute to the pathogenesis and diagnosis of ASD.
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28
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Vasu MM, Sumitha PS, Rahna P, Thanseem I, Anitha A. microRNAs in Autism Spectrum Disorders. Curr Pharm Des 2020; 25:4368-4378. [PMID: 31692427 DOI: 10.2174/1381612825666191105120901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 10/31/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Efforts to unravel the extensive impact of the non-coding elements of the human genome on cell homeostasis and pathological processes have gained momentum over the last couple of decades. miRNAs refer to short, often 18-25 nucleotides long, non-coding RNA molecules which can regulate gene expression. Each miRNA can regulate several mRNAs. METHODS This article reviews the literature on the roles of miRNAs in autism. RESULTS Considering the fact that ~ 1% of the human DNA encodes different families of miRNAs, their overall impact as critical regulators of gene expression in the mammalian brain should be immense. Though the autism spectrum disorders (ASDs) are predominantly genetic in nature and several candidate genes are already identified, the highly heterogeneous and multifactorial nature of the disorder makes it difficult to identify common genetic risk factors. Several studies have suggested that the environmental factors may interact with the genetic factors to increase the risk. miRNAs could possibly be one of those factors which explain this link between genetics and the environment. CONCLUSION In the present review, we have summarized our current knowledge on miRNAs and their complex roles in ASD, and also on their therapeutic applications.
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Affiliation(s)
- Mahesh Mundalil Vasu
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Puthiripadath S Sumitha
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Parakkal Rahna
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Ismail Thanseem
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Ayyappan Anitha
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
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29
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van Loo KMJ, Becker AJ. Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies. Front Cell Neurosci 2020; 13:587. [PMID: 31992970 PMCID: PMC6971179 DOI: 10.3389/fncel.2019.00587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/23/2019] [Indexed: 01/03/2023] Open
Abstract
Epilepsy is a common neurological disorder characterized by recurrent uncontrolled seizures and has an idiopathic “genetic” etiology or a symptomatic “acquired” component. Genetic studies have revealed that many epilepsy susceptibility genes encode ion channels, including voltage-gated sodium, potassium and calcium channels. The high prevalence of ion channels in epilepsy pathogenesis led to the causative concept of “ion channelopathies,” which can be elicited by specific mutations in the coding or promoter regions of genes in genetic epilepsies. Intriguingly, expression changes of the same ion channel genes by augmentation of specific transcription factors (TFs) early after an insult can underlie acquired epilepsies. In this study, we review how the transcriptional regulation of ion channels in both genetic and acquired epilepsies can be controlled, and compare these epilepsy “ion channelopathies” with other neurodevelopmental disorders.
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Affiliation(s)
- Karen M J van Loo
- Department of Neuropathology, Section for Translational Epilepsy Research, University of Bonn Medical Center, Bonn, Germany
| | - Albert J Becker
- Department of Neuropathology, Section for Translational Epilepsy Research, University of Bonn Medical Center, Bonn, Germany
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New Horizons for Molecular Genetics Diagnostic and Research in Autism Spectrum Disorder. ADVANCES IN NEUROBIOLOGY 2020; 24:43-81. [PMID: 32006356 DOI: 10.1007/978-3-030-30402-7_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autism spectrum disorder (ASD) is a highly heritable, heterogeneous, and complex pervasive neurodevelopmental disorder (PND) characterized by distinctive abnormalities of human cognitive functions, social interaction, and speech development.Nowadays, several genetic changes including chromosome abnormalities, genetic variations, transcriptional epigenetics, and noncoding RNA have been identified in ASD. However, the association between these genetic modifications and ASDs has not been confirmed yet.The aim of this review is to summarize the key findings in ASD from genetic viewpoint that have been identified from the last few decades of genetic and molecular research.
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Hu Z, Ying X, Huang L, Zhao Y, Zhou D, Liu J, Zhong J, Huang T, Zhang W, Cheng F, Duan S. Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder. Medicine (Baltimore) 2020; 99:e18838. [PMID: 31977880 PMCID: PMC7004686 DOI: 10.1097/md.0000000000018838] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Human serotonin receptor 4 (HTR4) encodes a 5-HT4 receptor involved in learning, memory, depression, anxiety, and feeding behavior. The aim of this study was to investigate the association between the deoxyribonucleic acid (DNA) methylation of HTR4 promoter and autism spectrum disorder (ASD), a disease characterized by communication disorder and repetitive or restrictive behavior.Peripheral blood DNA was obtained from 61 ASD children and 66 healthy children, and the DNA methylation of HTR4 promoter was assessed by quantitative methylation-specific polymerase chain reaction. We used percentage of methylated reference (PMR) to represent DNA methylation level.Due to significant age differences between ASD cases and controls (3 [2, 5] years and 6 [5, 6] years, P = 3.34E-10), we used binary logistic regression analysis for adjustment. Our results showed that the DNA methylation levels of HTR4 promoter were significantly lower in children with ASD than in healthy children (median PMR: 66.23% vs 94.31%,P = .028, age-adjusted P = .034). In addition, the DNA methylation of HTR4 promoter was inversely associated with age in male ASD cases (total cases: r = -0.283, P = .027; male cases: r = -0.431, P = .002; female cases: r = -0.108, P = .752). Dual-luciferase reporter gene assay showed that the reporter gene expression in the strain with recombinant pGL3-promoter-HTR4 plasmid was significantly higher than that in the strain with pGL3-promoter plasmid (fold change = 2.01, P = .0065), indicating that the HTR4 promoter fragment may contain transcription factors to upregulate promoter activity.Our study suggested that hypomethylation of the HTR4 promoter is a potential biomarker for predicting the risk of male ASD.
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Affiliation(s)
- Zhenyu Hu
- Ningbo Kangning Hospital, Ningbo Key Laboratory of Behavioral Neuroscience
| | - Xiuru Ying
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Ling Huang
- Ningbo Kangning Hospital, Ningbo Key Laboratory of Behavioral Neuroscience
| | - Yuanzhi Zhao
- Ningbo Kangning Hospital, Ningbo Key Laboratory of Behavioral Neuroscience
| | - Dongsheng Zhou
- Ningbo Kangning Hospital, Ningbo Key Laboratory of Behavioral Neuroscience
| | - Jing Liu
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Jie Zhong
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Tianyi Huang
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Wenwu Zhang
- Ningbo Kangning Hospital, Ningbo Key Laboratory of Behavioral Neuroscience
| | - Fang Cheng
- Ningbo Kangning Hospital, Ningbo Key Laboratory of Behavioral Neuroscience
| | - Shiwei Duan
- Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang, China
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MicroRNAs and Child Neuropsychiatric Disorders: A Brief Review. Neurochem Res 2019; 45:232-240. [DOI: 10.1007/s11064-019-02917-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 10/23/2019] [Accepted: 11/21/2019] [Indexed: 12/12/2022]
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Zhang SF, Gao J, Liu CM. The Role of Non-Coding RNAs in Neurodevelopmental Disorders. Front Genet 2019; 10:1033. [PMID: 31824553 PMCID: PMC6882276 DOI: 10.3389/fgene.2019.01033] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 09/25/2019] [Indexed: 12/24/2022] Open
Abstract
Non-coding RNAs, a group of ribonucleic acids that are ubiquitous in the body and do not encode proteins, emerge as important regulatory factors in almost all biological processes in the brain. Extensive studies have suggested the involvement of non-coding RNAs in brain development and neurodevelopmental disorders, and dysregulation of non-coding RNAs is associated with abnormal brain development and the etiology of neurodevelopmental disorders. Here we provide an overview of the roles and working mechanisms of non-coding RNAs, and discuss potential clinical applications of non-coding RNAs as diagnostic and prognostic markers and as therapeutic targets in neurodevelopmental disorders.
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Affiliation(s)
- Shuang-Feng Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
- School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Jun Gao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences & Peking Union Medical College, Beijing, China
| | - Chang-Mei Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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Salloum-Asfar S, Satheesh NJ, Abdulla SA. Circulating miRNAs, Small but Promising Biomarkers for Autism Spectrum Disorder. Front Mol Neurosci 2019; 12:253. [PMID: 31680857 PMCID: PMC6808050 DOI: 10.3389/fnmol.2019.00253] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 09/30/2019] [Indexed: 12/14/2022] Open
Abstract
Autism spectrum disorder (ASD) refers to a heterogeneous group of complex neurodevelopmental disorders characterized by social skill and communication deficits, along with stereotyped repetitive behavior. miRNAs, small non-coding RNAs that have been recognized as critical regulators of gene expression, play a key role in the neurodevelopmental transcriptional networks of the human brain. Previous investigations have proven that circulating miRNAs open up new possibilities for the emerging roles of diagnostic and prognostic biomarkers in human disorders and diseases. Biomarker development has been progressively becoming more recognized as a cornerstone in medical diagnosis, paving the way to drug discoveries and limiting the progression of various diseases. Due to the complexity of ASD, considerable endeavors have either unsuccessfully identified biomarkers for the disorder or have not yet been established. Cell-free circulating miRNAs in biofluids are extraordinarily stable and considered to represent the next-generation of clinical, non-invasive, biomarkers for many pathologies including neurological and neurodevelopmental disorders. Here, we conducted a review of all peer-reviewed articles addressing the circulating profiles of miRNAs, mostly performed in serum and saliva samples in individuals with ASD.
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Affiliation(s)
- Salam Salloum-Asfar
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Noothan J Satheesh
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Sara A Abdulla
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
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Assessment of Apoptosis Pathway in Peripheral Blood of Autistic Patients. J Mol Neurosci 2019; 69:588-596. [PMID: 31363911 DOI: 10.1007/s12031-019-01387-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 07/17/2019] [Indexed: 01/17/2023]
Abstract
Autism spectrum disorder (ASD) includes a number of severe neurodevelopmental disorders known by defects in social interaction, impaired verbal and non-verbal interactions, and stereotypic activities and limited interests. Dysregulation of apoptotic pathways have been demonstrated in brain tissues of affected individuals. In the present study, we evaluated expression levels of apoptosis-related genes and miRNAs in peripheral blood of ASD patients compared with healthy subjects. Transcript levels of BCL2, CASP8, and hsa-29c-3p were significantly lower in total ASD patients compared with total normal children (P values = 0.003, 0.002, and 0.01 respectively). When sex of study participants was considered in the analysis, the difference in transcript levels of these genes was significant only in male subjects. Peripheral expression of BCL2 and hsa-29c-3p had 100% sensitivity 92% specificity in ASD diagnosis. The diagnostic power of combination of transcript levels of these genes was estimated to be 78% based on the calculated AUC value. The present study provides evidences for dysregulation of apoptotic pathways in peripheral blood of ASD patients and suggests certain apoptosis-related genes as biomarkers in this regard.
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Alagoz M, Kherad N, Gavaz M, Yuksel A. New Genetic Approaches for Early Diagnosis and Treatment of Autism Spectrum Disorders. REVIEW JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS 2019. [DOI: 10.1007/s40489-019-00167-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Schmidt M, Lax E, Zhou R, Cheishvili D, Ruder AM, Ludiro A, Lapert F, Macedo da Cruz A, Sandrini P, Calzoni T, Vaisheva F, Brandwein C, Luoni A, Massart R, Lanfumey L, Riva MA, Deuschle M, Gass P, Szyf M. Fetal glucocorticoid receptor (Nr3c1) deficiency alters the landscape of DNA methylation of murine placenta in a sex-dependent manner and is associated to anxiety-like behavior in adulthood. Transl Psychiatry 2019; 9:23. [PMID: 30655507 PMCID: PMC6336883 DOI: 10.1038/s41398-018-0348-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 11/13/2018] [Indexed: 12/28/2022] Open
Abstract
Prenatal stress defines long-term phenotypes through epigenetic programming of the offspring. These effects are potentially mediated by glucocorticoid release and by sex. We hypothesized that the glucocorticoid receptor (Gr, Nr3c1) fashions the DNA methylation profile of offspring. Consistent with this hypothesis, fetal Nr3c1 heterozygosity leads to altered DNA methylation landscape in fetal placenta in a sex-specific manner. There was a significant overlap of differentially methylated genes in fetal placenta and adult frontal cortex in Nr3c1 heterozygotes. Phenotypically, Nr3c1 heterozygotes show significantly more anxiety-like behavior than wildtype. DNA methylation status of fetal placental tissue is significantly correlated with anxiety-like behavior of the same animals in adulthood. Thus, placental DNA methylation might predict behavioral phenotypes in adulthood. Our data supports the hypothesis that Nr3c1 influences DNA methylation at birth and that DNA methylation in placenta correlates with adult frontal cortex DNA methylation and anxiety-like phenotypes.
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Affiliation(s)
- Michaela Schmidt
- Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
| | - Elad Lax
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC H3G 1Y6 Canada ,0000 0004 1936 8649grid.14709.3bSackler Program for Epigenetics and Psychobiology, McGill University, Montreal, QC H3G 1Y6 Canada
| | - Rudy Zhou
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC H3G 1Y6 Canada
| | - David Cheishvili
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC H3G 1Y6 Canada ,0000 0004 1936 8649grid.14709.3bSackler Program for Epigenetics and Psychobiology, McGill University, Montreal, QC H3G 1Y6 Canada
| | - Arne Mathias Ruder
- 0000 0001 2190 4373grid.7700.0Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| | - Alessia Ludiro
- 0000 0004 1757 2822grid.4708.bDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti, 9, I-20133 Milan, Italy
| | - Florian Lapert
- 0000 0001 2190 4373grid.7700.0Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| | - Anna Macedo da Cruz
- 0000 0001 2190 4373grid.7700.0Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| | - Paolo Sandrini
- 0000 0004 1757 2822grid.4708.bDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti, 9, I-20133 Milan, Italy
| | - Teresa Calzoni
- 0000 0004 1757 2822grid.4708.bDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti, 9, I-20133 Milan, Italy
| | - Farida Vaisheva
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC H3G 1Y6 Canada
| | - Christiane Brandwein
- 0000 0001 2190 4373grid.7700.0Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| | - Alessia Luoni
- 0000 0004 1757 2822grid.4708.bDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti, 9, I-20133 Milan, Italy
| | - Renaud Massart
- 0000 0004 1936 8649grid.14709.3bSackler Program for Epigenetics and Psychobiology, McGill University, Montreal, QC H3G 1Y6 Canada ,0000 0004 0638 6979grid.417896.5Inserm, U894, Centre de Psychiatrie et Neurosciences, 75014 Paris, France
| | - Laurence Lanfumey
- 0000 0004 0638 6979grid.417896.5Inserm, U894, Centre de Psychiatrie et Neurosciences, 75014 Paris, France ,0000 0001 2188 0914grid.10992.33Université Paris Descartes, UMRS894, 75014 Paris, France
| | - Marco Andrea Riva
- 0000 0004 1757 2822grid.4708.bDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti, 9, I-20133 Milan, Italy
| | - Michael Deuschle
- 0000 0001 2190 4373grid.7700.0Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| | - Peter Gass
- 0000 0001 2190 4373grid.7700.0Central Institute of Mental Health Mannheim (ZI), Medical Faculty of Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany
| | - Moshe Szyf
- 0000 0004 1936 8649grid.14709.3bDepartment of Pharmacology & Therapeutics, McGill University, Montreal, QC H3G 1Y6 Canada ,0000 0004 1936 8649grid.14709.3bSackler Program for Epigenetics and Psychobiology, McGill University, Montreal, QC H3G 1Y6 Canada
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Tonacci A, Bagnato G, Pandolfo G, Billeci L, Sansone F, Conte R, Gangemi S. MicroRNA Cross-Involvement in Autism Spectrum Disorders and Atopic Dermatitis: A Literature Review. J Clin Med 2019; 8:jcm8010088. [PMID: 30646527 PMCID: PMC6352260 DOI: 10.3390/jcm8010088] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 12/27/2018] [Accepted: 01/11/2019] [Indexed: 12/16/2022] Open
Abstract
Autism Spectrum Disorder (ASD) is a category of neurodevelopmental disturbances seriously affecting social skills, to which the scientific community has paid great attention in last decades. To date, their pathogenesis is still unknown, but several studies highlighted the relevance of gene-environment interactions in the onset of ASD. In addition, an immune involvement was seen in a wide number of ASD subjects, leading several researchers to hypothesize a possible common pathogenesis between ASD and immune disturbances, including Atopic Dermatitis (AD). In general, among potential contributing factors, microRNAs (miRNAs), small molecules capable of controlling gene expression and targeting mRNA transcripts, might represent one of the major circulating link, possibly unraveling the connections between neurodevelopmental and immune conditions. Under such premises, we conducted a systematic literature review, under the PRISMA guidelines, trying to define the panel of common miRNAs involved in both ASD and AD. The review retrieved articles published between January 1, 2005, and December 13, 2018, in PubMed, ScienceDirect, PsycARTICLES, and Google Scholar. We found a handful of works dealing with miRNAs in ASD and AD, with the most overlapping dysregulated miRNAs being miR-146 and miR-155. Two possible compounds are abnormally regulated in both ASD and AD subjects, possibly cross-contributing to the interactions between the two disorders, setting the basis to investigate more precisely the possible link between ASD and AD from another, not just clinical, perspective.
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Affiliation(s)
- Alessandro Tonacci
- Clinical Physiology Institute-National Research Council of Italy (IFC-CNR), Via Moruzzi 1, 56124 Pisa, Italy.
| | - Gianluca Bagnato
- School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria SNC, 98125 Messina, Italy.
| | - Gianluca Pandolfo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.
| | - Lucia Billeci
- Clinical Physiology Institute-National Research Council of Italy (IFC-CNR), Via Moruzzi 1, 56124 Pisa, Italy.
| | - Francesco Sansone
- Clinical Physiology Institute-National Research Council of Italy (IFC-CNR), Via Moruzzi 1, 56124 Pisa, Italy.
| | - Raffaele Conte
- Clinical Physiology Institute-National Research Council of Italy (IFC-CNR), Via Moruzzi 1, 56124 Pisa, Italy.
| | - Sebastiano Gangemi
- School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University Hospital "G. Martino", Via Consolare Valeria SNC, 98125 Messina, Italy.
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Wiśniowiecka-Kowalnik B, Nowakowska BA. Genetics and epigenetics of autism spectrum disorder-current evidence in the field. J Appl Genet 2019; 60:37-47. [PMID: 30627967 PMCID: PMC6373410 DOI: 10.1007/s13353-018-00480-w] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/14/2018] [Accepted: 12/18/2018] [Indexed: 12/26/2022]
Abstract
Autism spectrum disorders (ASD) is a heterogenous group of neurodevelopmental disorders characterized by problems in social interaction and communication as well as the presence of repetitive and stereotyped behavior. It is estimated that the prevalence of ASD is 1–2% in the general population with the average male to female ratio 4–5:1. Although the causes of ASD remain largely unknown, the studies have shown that both genetic and environmental factors play an important role in the etiology of these disorders. Array comparative genomic hybridization and whole exome/genome sequencing studies identified common and rare copy number or single nucleotide variants in genes encoding proteins involved in brain development, which play an important role in neuron and synapse formation and function. The genetic etiology is recognized in ~ 25–35% of patients with ASD. In this article, we review the current state of knowledge about the genetic etiology of ASD and also propose a diagnostic algorithm for patients.
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Moosa A, Shu H, Sarachana T, Hu VW. Are endocrine disrupting compounds environmental risk factors for autism spectrum disorder? Horm Behav 2018; 101:13-21. [PMID: 29042182 PMCID: PMC5913002 DOI: 10.1016/j.yhbeh.2017.10.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/25/2017] [Accepted: 10/10/2017] [Indexed: 11/30/2022]
Abstract
Recent research on the etiology of autism spectrum disorder (ASD) has shifted in part from a singular focus on genetic causes to the involvement of environmental factors and their gene interactions. This shift in focus is a result of the rapidly increasing prevalence of ASD coupled with the incomplete penetrance of this disorder in monozygotic twins. One such area of environmentally focused research is the association of exposures to endocrine disrupting compounds (EDCs) with elevated risk for ASD. EDCs are exogenous chemicals that can alter endogenous hormone activity and homeostasis, thus potentially disrupting the action of sex and other natural hormones at all stages of human development. Inasmuch as sex hormones play a fundamental role in brain development and sexual differentiation, exposure to EDCs in utero during critical stages of development can have lasting neurological and other physiological influences on the developing fetus and, ultimately, the child as well as adult. This review will focus on the possible contributions of EDCs to autism risk and pathogenesis by first discussing the influence of endogenous sex hormones on the autistic phenotype, followed by a review of documented human exposures to EDCs and associations with behaviors relevant to ASD. Mechanistic links between EDC exposures and aberrant neurodevelopment and behaviors are then considered, with emphasis on EDC-induced transcriptional profiles derived from animal and cellular studies. Finally, this review will discuss possible mechanisms through which EDC exposure can lead to persistent changes in gene expression and phenotype, which may in turn contribute to transgenerational inheritance of ASD.
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Affiliation(s)
- Amer Moosa
- Dept. of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye St., NW, Washington, DC 20037, United States.
| | - Henry Shu
- Dept. of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye St., NW, Washington, DC 20037, United States.
| | - Tewarit Sarachana
- Department of Clinical Chemistry, Medical Technology Branch, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Rama I Rd., Wangmai, Pathumwan, Bangkok 10330, Thailand.
| | - Valerie W Hu
- Dept. of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye St., NW, Washington, DC 20037, United States.
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Aushev VN, Lee E, Zhu J, Gopalakrishnan K, Li Q, Teitelbaum SL, Wetmur J, Degli Esposti D, Hernandez-Vargas H, Herceg Z, Parada H, Santella RM, Gammon MD, Chen J. Novel Predictors of Breast Cancer Survival Derived from miRNA Activity Analysis. Clin Cancer Res 2018; 24:581-591. [PMID: 29138345 PMCID: PMC6103440 DOI: 10.1158/1078-0432.ccr-17-0996] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/21/2017] [Accepted: 11/10/2017] [Indexed: 01/14/2023]
Abstract
Purpose: Breast cancer is among the leading causes of cancer-related death; discovery of novel prognostic markers is needed to improve outcomes. Combining systems biology and epidemiology, we investigated miRNA-associated genes and breast cancer survival in a well-characterized population-based study.Experimental Design: A recently developed algorithm, ActMiR, was used to identify key miRNA "activities" corresponding to target gene degradation, which were predictive of breast cancer mortality in published databases. We profiled miRNA-associated genes in tumors from our well-characterized population-based cohort of 606 women with first primary breast cancer. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI), after 15+ years of follow-up with 119 breast cancer-specific deaths.Results: miR-500a activity was identified as a key miRNA for estrogen receptor-positive breast cancer mortality using public databases. From a panel of 161 miR-500a-associated genes profiled, 73 were significantly associated with breast cancer-specific mortality (FDR < 0.05) in our population, among which two clusters were observed to have opposing directions of association. For example, high level of SUSD3 was associated with reduced breast cancer-specific mortality (HR = 0.3; 95% CI, 0.2-0.4), whereas the opposite was observed for TPX2 (HR = 2.7; 95% CI, 1.8-3.9). Most importantly, we identified set of genes for which associations with breast cancer-specific mortality were independent of known prognostic factors, including hormone receptor status and PAM50-derived risk-of-recurrence scores. These results are validated in independent datasets.Conclusions: We identified novel markers that may improve prognostic efficiency while shedding light on molecular mechanisms of breast cancer progression. Clin Cancer Res; 24(3); 581-91. ©2017 AACR.
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Affiliation(s)
- Vasily N Aushev
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
- Carcinogenesis Institute of N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
| | - Eunjee Lee
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jun Zhu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kalpana Gopalakrishnan
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Qian Li
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Susan L Teitelbaum
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
| | - James Wetmur
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | | | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer, Lyon, France
| | - Humberto Parada
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Regina M Santella
- Department of Environmental Health Sciences, Columbia University, New York, New York
| | - Marilie D Gammon
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jia Chen
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York.
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
- Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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