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Julie AOJ, Bébé NO, Sandrine MNY, Emmanuel OP, Antoine KK, Dupon AAB, Cicilien NPQ, Emmanuel NNF, Laure NJ, Claude BD, Désiré DDP. Phytochemical, In Silico, In Vitro, and In Vivo Research on Piptadeniastrum africanum (Fabaceae) Unveiling Anti-Stereotypic, Anxiolytic, and Analgesic Effects in a Sodium Valproate-Induced Autistic Disorders Model. Brain Behav 2025; 15:e70408. [PMID: 40079500 PMCID: PMC11904952 DOI: 10.1002/brb3.70408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/05/2025] [Accepted: 02/14/2025] [Indexed: 03/15/2025] Open
Abstract
OBJECTIVE Individuals with autistic spectrum disorders (ASD) primarily exhibit deficits in communication and social interaction, along with repetitive behaviors and restricted interests. This disorder is often associated with anxiety, nociceptive disorders, and pain. While medical treatment generally focuses on treating the symptoms rather than addressing the underlying causes, traditional medicine is sometimes used as an alternative. Piptadeniastrum africanum is used in Cameroonian medicinal folks to treat cognitive disorders. However, its effects and mechanisms of action regarding the inhibition of ASD-like symptoms remain unclear. The primary goal of the present study was to evaluate the anxiolytic and analgesic effects of the water extract of P. africanum on autistic triad induced in rats by sodium valproate. MATERIAL AND METHODS The study investigated the secondary metabolites in P. africanum extract using UHPLC-MS. DPPH, ABTS, and FRAP tests were performed to assess the extract's ability to neutralize free radicals. Molecular docking was utilized to evaluate the extract's binding to various receptors. For the experimental study, 33 pregnant female rats were divided into two groups after pregnancy was confirmed. One group was given distilled water orally at 10 mL/kg, while the other group received sodium valproate at 800 mg/kg on gestation days 11, 12, and 13. When the male offspring reached 3 weeks old, they were evaluated for anxiety, social interaction, and pain sensitivity, with those displaying any disorders selected for further study. The remaining rats were split into six groups of five and treated with either a vehicle, bumetanide, or P. africanum extract at 190 and 760 mg/kg. Behavioral assessments focusing on sociability, anxiety, and pain sensitivity were conducted on days 28 and 37 after weaning. In the end, biochemical markers related to GABA metabolism, serotonin levels, and oxidative status were analyzed in the cerebellum, prefrontal cortex, hippocampus, and amygdala alongside histopathological analyses in the brain. RESULTS UHPLC-MS allows us to identify several compounds. They bind to H3R (7F61) and HDAC2 through conventional hydrogen bonding. Findings showed that prenatal administration of sodium valproate induced in male offspring a deficit in social interaction (p < 0.001), anxiety disorders (p < 0.001), hypersensitivity to pain (p < 0.001), increased GABA and serotonin concentration (p < 0.001), disturbed oxidative status (p < 0.001), and neuronal loss (p < 0.001) as well as neuronal disorganization in the hippocampus, cerebellum and amygdala in young rats compared to neurotypical animals. P. africanum extract at doses used, like bumetanide, corrected these disorders and protected against neuronal loss. These results suggest that the extract has anxiolytic and anti-nociceptive effects. It has been found that the positive effects can be achieved by restoring GABAergic and serotonergic neurotransmission, coupled with antioxidant and neuromodulatory activity. CONCLUSION The current findings support that P. africanum induces anxiolytic and analgesic effects in a sodium valproate-induced autistic disorders model.
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Affiliation(s)
- Ambani Omgba Jeanne Julie
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Ngouateu Omer Bébé
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Mengue Ngadena Yolande Sandrine
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
- Neurosciences axis, Laboratory of Development and Maldevelopment, Department of Psychology, Faculty of Arts, Letters, and Social ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Owona Pascal Emmanuel
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Kandeda Kavaye Antoine
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Ambamba Akamba Bruno Dupon
- Department of Biochemistry, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
- Center of Nutrition and Functional FoodsYaoundéCameroon
| | | | - Ngang Nguema Franck Emmanuel
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Ngondi Judith Laure
- Department of Biochemistry, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
- Center of Nutrition and Functional FoodsYaoundéCameroon
| | - Bilanda Danielle Claude
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
| | - Dzeufiet Djomeni Paul Désiré
- Department of Animal Biology and Physiology, Laboratory of Animal Physiology, Faculty of ScienceUniversity of Yaoundé 1YaoundéCameroon
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Roberts CT, Raabe N, Wiegand L, Kadar Shahib A, Rastegar M. Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease. Pharmaceuticals (Basel) 2024; 17:1601. [PMID: 39770443 PMCID: PMC11677501 DOI: 10.3390/ph17121601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
Metformin is a commonly used drug for treating type 2 diabetes. Metformin is an inexpensive drug with low/no side effects and is well tolerated in human patients of different ages. Recent therapeutic strategies for human disease have considered the benefits of drug repurposing. This includes the use of the anti-diabetic drug metformin. Accordingly, the anti-inflammatory, anti-cancer, anti-viral, neuroprotective, and cardioprotective potentials of metformin have deemed it a suitable candidate for treating a plethora of human diseases. As results from preclinical studies using cellular and animal model systems appear promising, clinical trials with metformin in the context of non-diabetes-related illnesses have been started. Here, we aim to provide a comprehensive overview of the therapeutic potential of metformin in different animal models of human disease and its suggested relationship to epigenetics and ailments with epigenetic components.
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Affiliation(s)
| | | | | | | | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Di Gesù CM, Buffington SA. The early life exposome and autism risk: a role for the maternal microbiome? Gut Microbes 2024; 16:2385117. [PMID: 39120056 PMCID: PMC11318715 DOI: 10.1080/19490976.2024.2385117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 08/10/2024] Open
Abstract
Autism spectrum disorders (ASD) are highly heritable, heterogeneous neurodevelopmental disorders characterized by clinical presentation of atypical social, communicative, and repetitive behaviors. Over the past 25 years, hundreds of ASD risk genes have been identified. Many converge on key molecular pathways, from translational control to those regulating synaptic structure and function. Despite these advances, therapeutic approaches remain elusive. Emerging data unearthing the relationship between genetics, microbes, and immunity in ASD suggest an integrative physiology approach could be paramount to delivering therapeutic breakthroughs. Indeed, the advent of large-scale multi-OMIC data acquisition, analysis, and interpretation is yielding an increasingly mechanistic understanding of ASD and underlying risk factors, revealing how genetic susceptibility interacts with microbial genetics, metabolism, epigenetic (re)programming, and immunity to influence neurodevelopment and behavioral outcomes. It is now possible to foresee exciting advancements in the treatment of some forms of ASD that could markedly improve quality of life and productivity for autistic individuals. Here, we highlight recent work revealing how gene X maternal exposome interactions influence risk for ASD, with emphasis on the intrauterine environment and fetal neurodevelopment, host-microbe interactions, and the evolving therapeutic landscape for ASD.
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Affiliation(s)
- Claudia M. Di Gesù
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA
| | - Shelly A. Buffington
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
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Yurdakul E, Barlas Y, Ulgen KO. Circadian clock crosstalks with autism. Brain Behav 2023; 13:e3273. [PMID: 37807632 PMCID: PMC10726833 DOI: 10.1002/brb3.3273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 09/10/2023] [Accepted: 09/24/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND The mechanism underlying autism spectrum disorder (ASD) remains incompletely understood, but researchers have identified over a thousand genes involved in complex interactions within the brain, nervous, and immune systems, particularly during the mechanism of brain development. Various contributory environmental effects including circadian rhythm have also been studied in ASD. Thus, capturing the global picture of the ASD-clock network in combined form is critical. METHODS We reconstructed the protein-protein interaction network of ASD and circadian rhythm to understand the connection between autism and the circadian clock. A graph theoretical study is undertaken to evaluate whether the network attributes are biologically realistic. The gene ontology enrichment analyses provide information about the most important biological processes. RESULTS This study takes a fresh look at metabolic mechanisms and the identification of potential key proteins/pathways (ribosome biogenesis, oxidative stress, insulin/IGF pathway, Wnt pathway, and mTOR pathway), as well as the effects of specific conditions (such as maternal stress or disruption of circadian rhythm) on the development of ASD due to environmental factors. CONCLUSION Understanding the relationship between circadian rhythm and ASD provides insight into the involvement of these essential pathways in the pathogenesis/etiology of ASD, as well as potential early intervention options and chronotherapeutic strategies for treating or preventing the neurodevelopmental disorder.
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Affiliation(s)
- Ekin Yurdakul
- Department of Chemical EngineeringBogazici University, Biosystems Engineering LaboratoryIstanbulTurkey
| | - Yaman Barlas
- Department of Industrial EngineeringBogazici University, Socio‐Economic System Dynamics Research Group (SESDYN)IstanbulTurkey
| | - Kutlu O. Ulgen
- Department of Chemical EngineeringBogazici University, Biosystems Engineering LaboratoryIstanbulTurkey
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Sun R, Guo P, Sun T, Yu H, Liao Y, Xie J, Zeng J, Xie X, Huang S. Sex hormone receptor expression in children with autism spectrum disorder.. [DOI: 10.21203/rs.3.rs-2345028/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Abstract
Background
Sex hormones, especially estrogen, which binds to estrogen receptor β (ERβ), play a vital role in the pathogenesis of mental disorders such as autism spectrum disorder (ASD). The purpose of this study was to analyze the serum levels of hormone receptors, including ERβ, progesterone receptor (PGR) and androgen receptor (AR), and compare these levels between children with ASD and typically developing (TD) children. We also investigated the relationships of ERβ mRNA levels with ASD core symptoms, sleep, and developmental quotients (DQs) from the Gesell Developmental Schedules (GDS) among children with ASD.
Methods
We compared the mRNA levels of ERβ, AR, and PGR between 56 children with ASD and 37 TD children by using quantitative real-time PCR. Then, a correlation analysis was performed to determine the correlations of ERβ mRNA levels with Childhood Autism Rating Scale (CARS), Autism Behavior Checklist (ABC), and Children’s Sleep Habits Questionnaire (CHSQ) scores as well as DQs among ASD children.
Results
We found that serum mRNA levels of ERβ in ASD children were significantly lower than those in the TD group. However, we found no correlations of the ERβ mRNA level with CARS, ABC, and CHSQ scores as well as DQs on each GDS domain among ASD children.
Conclusions
Elevated ERβ mRNA levels in peripheral blood may be related to ASD but this association needs to be validated with a larger sample size.
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Affiliation(s)
- Ruoyu Sun
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Pi Guo
- Shantou University Medical College
| | - Tao Sun
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Hong Yu
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Yanwei Liao
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Jieqi Xie
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Jiaying Zeng
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Xiaoyun Xie
- Foshan Maternal and Child Health Hospital, Southern Medical University
| | - Saijun Huang
- Foshan Maternal and Child Health Hospital, Southern Medical University
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Maternal treatment with sodium butyrate reduces the development of autism-like traits in mice offspring. Biomed Pharmacother 2022; 156:113870. [DOI: 10.1016/j.biopha.2022.113870] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/09/2022] [Accepted: 10/13/2022] [Indexed: 11/18/2022] Open
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Jaureguiberry MS, Venturino A. Nutritional and environmental contributions to Autism Spectrum Disorders: Focus on nutrigenomics as complementary therapy. INT J VITAM NUTR RES 2020; 92:248-266. [PMID: 32065556 DOI: 10.1024/0300-9831/a000630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The prevalence of autism spectrum disorders (ASD) has risen sharply in the last 30 years, posing a major public health concern and a big emotional and financial challenge for families. While the underlying causes remain to be fully elucidated, evidence shows moderate genetic heritability contribution, but heavy environmental influence. Over the last decades, modern lifestyle has deeply changed our eating, rest, and exercise habits, while exposure to air, water, and food chemical pollution has increased due to indiscriminate use of pesticides, food additives, adjuvants, and antibiotics. The result is a drastic change in the quality of our energy source input, and an overload for antioxidant and detoxification pathways that compromises normal metabolism and homeostasis. Current research shows high prevalence of food selectivity and/or food allergy among children with autism, resulting in essential micronutrient deficits that may trigger or aggravate physical and cognitive symptoms. Nutrigenomics is an emerging discipline that focuses on genotype-micronutrient interaction, and a useful approach to tailor low risk, personalized interventions through diet and micronutrient supplementation. Here, we review available literature addressing the role of micronutrients in the symptomatology of ASD, the metabolic pathways involved, and their therapeutic relevance. Personalized and supervised supplementation according to individual needs is suggested as a complement of traditional therapies to improve outcome both for children with autism and their families.
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Affiliation(s)
- María S Jaureguiberry
- Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue-CITAAC, Universidad Nacional del Comahue-CONICET, Neuquén, Argentina
| | - Andrés Venturino
- Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue-CITAAC, Universidad Nacional del Comahue-CONICET, Neuquén, Argentina
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Abstract
Research on autism and environmental risk factors has expanded substantially in recent years. My analysis draws attention to the regimes of perceptibility that shape how the environment is materialized in post-genomic science. I focus on how more complex narratives of autism's causes and social anxieties surrounding child development have helped situate autism risk in women's bodies before and during pregnancy. This has resulted in what I call the maternal body as environment in autism science. I show that this figure involves three characteristics: the molecularization of the environment, an individualization of risk, and the internalization of responsibility. I argue that these three features point to a new spatial and temporal politics of risk and responsibility that may heighten social and medical surveillance of women's bodies and decisions, eclipsing larger questions about the uneven distribution of exposures in society and more holistic understandings of health that include neurodiversity. I conclude by considering what the maternal body as environment signals for women, social justice, and the politics of environmental health in the post-genomic era.
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Affiliation(s)
- Martine Lappé
- Center for Research on Ethical, Legal and Social Implications of Psychiatric, Neurologic and Behavioral Genetics, Columbia University, New York, NY, USA
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Bergman NJ. Hypothesis on supine sleep, sudden infant death syndrome reduction and association with increasing autism incidence. World J Clin Pediatr 2016; 5:330-342. [PMID: 27610351 PMCID: PMC4978628 DOI: 10.5409/wjcp.v5.i3.330] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 05/26/2016] [Accepted: 06/03/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To identify a hypothesis on: Supine sleep, sudden infant death syndrome (SIDS) reduction and association with increasing autism incidence.
METHODS: Literature was searched for autism spectrum disorder incidence time trends, with correlation of change-points matching supine sleep campaigns. A mechanistic model expanding the hypothesis was constructed based on further review of epidemiological and other literature on autism.
RESULTS: In five countries (Denmark, United Kingdom, Australia, Israel, United States) with published time trends of autism, change-points coinciding with supine sleep campaigns were identified. The model proposes that supine sleep does not directly cause autism, but increases the likelihood of expression of a subset of autistic criteria in individuals with genetic susceptibility, thereby specifically increasing the incidence of autism without intellectual disability.
CONCLUSION: Supine sleep is likely a physiological stressor, that does reduce SIDS, but at the cost of impact on emotional and social development in the population, a portion of which will be susceptible to, and consequently express autism. A re-evaluation of all benefits and harms of supine sleep is warranted. If the SIDS mechanism proposed and autism model presented can be verified, the research agenda may be better directed, in order to further decrease SIDS, and reduce autism incidence.
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Foraker J, Millard SP, Leong L, Thomson Z, Chen S, Keene CD, Bekris LM, Yu CE. The APOE Gene is Differentially Methylated in Alzheimer's Disease. J Alzheimers Dis 2016; 48:745-55. [PMID: 26402071 DOI: 10.3233/jad-143060] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.
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Affiliation(s)
- Jessica Foraker
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.,Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA
| | - Steven P Millard
- Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Lesley Leong
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Zachary Thomson
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Sunny Chen
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
| | - C Dirk Keene
- Neuropathology Division, Department of Pathology, University of Washington, Seattle, WA, USA
| | - Lynn M Bekris
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland Ohio, USA
| | - Chang-En Yu
- Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.,Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA, USA
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Pagliaroli L, Vető B, Arányi T, Barta C. From Genetics to Epigenetics: New Perspectives in Tourette Syndrome Research. Front Neurosci 2016; 10:277. [PMID: 27462201 PMCID: PMC4940402 DOI: 10.3389/fnins.2016.00277] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 06/06/2016] [Indexed: 11/13/2022] Open
Abstract
Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome. This review provides a summary of the recent findings in genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS.
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Affiliation(s)
- Luca Pagliaroli
- Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis UniversityBudapest, Hungary; Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of SciencesBudapest, Hungary
| | - Borbála Vető
- Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences Budapest, Hungary
| | - Tamás Arányi
- Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of SciencesBudapest, Hungary; Centre National de la Recherche Scientifique UMR 6214, Institut National de la Santé et de la Recherche Médicale U1083, University of AngersAngers, France
| | - Csaba Barta
- Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University Budapest, Hungary
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Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder. Mol Psychiatry 2016; 21:426-36. [PMID: 26055422 DOI: 10.1038/mp.2015.64] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/02/2015] [Accepted: 04/27/2015] [Indexed: 02/07/2023]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene-environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition.
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Cacabelos R, Torrellas C. Epigenetics of Aging and Alzheimer's Disease: Implications for Pharmacogenomics and Drug Response. Int J Mol Sci 2015; 16:30483-543. [PMID: 26703582 PMCID: PMC4691177 DOI: 10.3390/ijms161226236] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 11/16/2015] [Accepted: 12/08/2015] [Indexed: 02/07/2023] Open
Abstract
Epigenetic variability (DNA methylation/demethylation, histone modifications, microRNA regulation) is common in physiological and pathological conditions. Epigenetic alterations are present in different tissues along the aging process and in neurodegenerative disorders, such as Alzheimer’s disease (AD). Epigenetics affect life span and longevity. AD-related genes exhibit epigenetic changes, indicating that epigenetics might exert a pathogenic role in dementia. Epigenetic modifications are reversible and can potentially be targeted by pharmacological intervention. Epigenetic drugs may be useful for the treatment of major problems of health (e.g., cancer, cardiovascular disorders, brain disorders). The efficacy and safety of these and other medications depend upon the efficiency of the pharmacogenetic process in which different clusters of genes (pathogenic, mechanistic, metabolic, transporter, pleiotropic) are involved. Most of these genes are also under the influence of the epigenetic machinery. The information available on the pharmacoepigenomics of most drugs is very limited; however, growing evidence indicates that epigenetic changes are determinant in the pathogenesis of many medical conditions and in drug response and drug resistance. Consequently, pharmacoepigenetic studies should be incorporated in drug development and personalized treatments.
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Affiliation(s)
- Ramón Cacabelos
- EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, 15165-Bergondo, Corunna, Spain.
- Chair of Genomic Medicine, Camilo José Cela University, 28692-Madrid, Spain.
| | - Clara Torrellas
- EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, 15165-Bergondo, Corunna, Spain.
- Chair of Genomic Medicine, Camilo José Cela University, 28692-Madrid, Spain.
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Wasilewska J, Klukowski M. Gastrointestinal symptoms and autism spectrum disorder: links and risks - a possible new overlap syndrome. Pediatric Health Med Ther 2015; 6:153-166. [PMID: 29388597 PMCID: PMC5683266 DOI: 10.2147/phmt.s85717] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Autism spectrum disorder (ASD) is a genetically determined neurodevelopmental brain disorder presenting with restricted, repetitive patterns of behaviors, interests, and activities, or persistent deficits in social communication and social interaction. ASD is characterized by many different clinical endophenotypes and is potentially linked with certain comorbidities. According to current recommendations, children with ASD are at risk of having alimentary tract disorders - mainly, they are at a greater risk of general gastrointestinal (GI) concerns, constipation, diarrhea, and abdominal pain. GI symptoms may overlap with ASD core symptoms through different mechanisms. These mechanisms include multilevel pathways in the gut-brain axis contributing to alterations in behavior and cognition. Shared pathogenetic factors and pathophysiological mechanisms possibly linking ASD and GI disturbances, as shown by most recent studies, include intestinal inflammation with or without autoimmunity, immunoglobulin E-mediated and/or cell-mediated GI food allergies as well as gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity linked with functional abdominal pain, and dysautonomia linked with GI dysmotility and gastroesophageal reflux. Dysregulation of the gut microbiome has also been shown to be involved in modulating GI functions with the ability to affect intestinal permeability, mucosal immune function, and intestinal motility and sensitivity. Metabolic activity of the microbiome and dietary components are currently suspected to be associated with alterations in behavior and cognition also in patients with other neurodegenerative diseases. All the above-listed GI factors may contribute to brain dysfunction and neuroinflammation depending upon an individual patient's genetic vulnerability. Due to a possible clinical endophenotype presenting as comorbidity of ASD and GI disorders, we propose treating this situation as an "overlap syndrome". Practical use of the concept of an overlap syndrome of ASD and GI disorders may help in identifying those children with ASD who suffer from an alimentary tract disease. Unexplained worsening of nonverbal behaviors (agitation, anxiety, aggression, self-injury, sleep deprivation) should alert professionals about this possibility. This may shorten the time to diagnosis and treatment commencement, and thereby alleviate both GI and ASD symptoms through reducing pain, stress, or discomfort. Furthermore, this may also protect children against unnecessary dietary experiments and restrictions that have no medical indications. A personalized approach to each patient is necessary. Our understanding of ASDs has come a long way, but further studies and more systematic research are warranted.
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Affiliation(s)
- Jolanta Wasilewska
- Department of Pediatrics, Gastroenterology and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Mark Klukowski
- Department of Pediatrics, Gastroenterology and Allergology, Medical University of Bialystok, Bialystok, Poland
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Warrier V, Chakrabarti B, Murphy L, Chan A, Craig I, Mallya U, Lakatošová S, Rehnstrom K, Peltonen L, Wheelwright S, Allison C, Fisher SE, Baron-Cohen S. A Pooled Genome-Wide Association Study of Asperger Syndrome. PLoS One 2015; 10:e0131202. [PMID: 26176695 PMCID: PMC4503355 DOI: 10.1371/journal.pone.0131202] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 05/30/2015] [Indexed: 12/27/2022] Open
Abstract
Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.
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Affiliation(s)
- Varun Warrier
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Bhismadev Chakrabarti
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
- School of Psychology and Clinical Language Sciences, Centre for Integrative Neuroscience and Neurodynamics, University of Reading, Reading, United Kingdom
| | - Laura Murphy
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Allen Chan
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Ian Craig
- MRC Centre for Social, Genetic and Developmental Psychiatry, King’s College London, Institute of Psychiatry, London, United Kingdom
| | - Uma Mallya
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Silvia Lakatošová
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Karola Rehnstrom
- The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom
| | - Leena Peltonen
- The Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom
| | - Sally Wheelwright
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Carrie Allison
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Simon E. Fisher
- Max Planck Institute for Psycholinguistics, 6500 AH, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Simon Baron-Cohen
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
- CLASS Clinic, Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Cambridge, United Kingdom
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Bai G, Ren K, Dubner R. Epigenetic regulation of persistent pain. Transl Res 2015; 165:177-99. [PMID: 24948399 PMCID: PMC4247805 DOI: 10.1016/j.trsl.2014.05.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/19/2014] [Accepted: 05/20/2014] [Indexed: 02/09/2023]
Abstract
Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling. Epigenetic regulation governs gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development or maintenance of persistent pain and possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain.
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Affiliation(s)
- Guang Bai
- Program in Neuroscience, Department of Neural and Pain Sciences, University of Maryland Dental School, University of Maryland, Baltimore, MD.
| | - Ke Ren
- Program in Neuroscience, Department of Neural and Pain Sciences, University of Maryland Dental School, University of Maryland, Baltimore, MD
| | - Ronald Dubner
- Program in Neuroscience, Department of Neural and Pain Sciences, University of Maryland Dental School, University of Maryland, Baltimore, MD
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Gámez-Del-Estal MM, Contreras I, Prieto-Pérez R, Ruiz-Rubio M. Epigenetic effect of testosterone in the behavior of C. elegans. A clue to explain androgen-dependent autistic traits? Front Cell Neurosci 2014; 8:69. [PMID: 24624060 PMCID: PMC3940884 DOI: 10.3389/fncel.2014.00069] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 02/17/2014] [Indexed: 12/04/2022] Open
Abstract
Current research indicates that the causes of autism spectrum disorders (ASDs) are multifactorial and include both genetic and environmental factors. To date, several works have associated ASDs with mutations in genes that encode proteins involved in neuronal synapses; however other factors and the way they can interact with the development of the nervous system remain largely unknown. Some studies have established a direct relationship between risk for ASDs and the exposure of the fetus to high testosterone levels during the prenatal stage. In this work, in order to explain possible mechanisms by which this androgenic hormone may interact with the nervous system, C. elegans was used as an experimental model. We observed that testosterone was able to alter the behavioral pattern of the worm, including the gentle touch response and the pharyngeal pumping rate. This impairment of the behavior was abolished using specific RNAi against genes orthologous to the human androgen receptor gene. The effect of testosterone was eliminated in the nhr-69 (ok1926) deficient mutant, a putative ortholog of human AR gene, suggesting that this gene encodes a receptor able to interact with the hormone. On the other hand the testosterone effect remained in the gentle touch response during four generations in the absence of the hormone, indicating that some epigenetic mechanisms could be involved. Sodium butyrate, a histone deacetylase inhibitor, was able to abolish the effect of testosterone. In addition, the lasting effect of testosterone was eliminated after the dauer stage. These results suggest that testosterone may impair the nervous system function generating transgenerational epigenetic marks in the genome. This work may provide new paradigms for understanding biological mechanisms involved in ASDs traits.
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Affiliation(s)
- M Mar Gámez-Del-Estal
- Departamento de Genética, Universidad de Córdoba, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba Córdoba, Spain
| | - Israel Contreras
- Departamento de Genética, Universidad de Córdoba, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba Córdoba, Spain
| | - Rocío Prieto-Pérez
- Departamento de Genética, Universidad de Córdoba, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba Córdoba, Spain
| | - Manuel Ruiz-Rubio
- Departamento de Genética, Universidad de Córdoba, Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba Córdoba, Spain
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