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1
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Pickard BS. A mechanism of global gene expression regulation is disrupted by multiple disease states and drug treatments. PLoS One 2025; 20:e0317071. [PMID: 40341320 PMCID: PMC12061403 DOI: 10.1371/journal.pone.0317071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 02/25/2025] [Indexed: 05/10/2025] Open
Abstract
Conventional expression studies quantify messenger RNA (mRNA) transcript levels gene-by-gene. We recently showed that protein expression is modulated at a global scale by amino acid availability, suggesting that mRNA expression levels might be equivalently affected. Through re-analysis of public transcriptomic datasets, it was confirmed that nucleobase supply interacts with the specific demands of mRNA A + U:C + G sequence composition to shape a global profile of expression, which can be quantified as a gradient of average expression change by average composition change. In mammals, each separate organ and cell-type displays a distinct baseline profile of global expression. These profiles can shift dynamically across the circadian day and the menstrual cycle. They are also significantly distorted by viral infection, multiple complex genetic disorders (including Alzheimer's disease, schizophrenia, and autoimmune disorders), and after treatment with 115 of the 597 chemical entities analysed. These included known toxins and nucleobase analogues, but also many commonly prescribed medications such as antibiotics and proton pump inhibitors, thus revealing a new mechanism of drug action and side-effect. As well as key roles in disease susceptibility, mRNAs with extreme compositions are significantly over-represented in gene ontologies such as transcription and cell division, making these processes particularly sensitive to swings in global expression. This may permit efficient, en bloc transcriptional reprogramming of cell state through simple adjustment of nucleobase proportion and supply. It is also proposed that this mechanism helped mitigate the loss of essential amino acid synthesis in higher organisms. In summary, global expression regulation is invisible to conventional transcriptomic analysis, but its measurement allows a useful distinction between active, promoter-mediated gene expression changes and passive, cell state-dependent transcriptional competence. Linking cell metabolism directly to gene expression offers an entirely new perspective on evolution, disease aetiopathology (including gene x environment - GxE - interactions), and the nature of the pharmacological response.
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Affiliation(s)
- Benjamin S. Pickard
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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2
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Natowicz MR, Bauman ML, Edelson SM. A most important gift: the critical role of postmortem brain tissue in autism science. Front Neurol 2024; 15:1486227. [PMID: 39726759 PMCID: PMC11670190 DOI: 10.3389/fneur.2024.1486227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 11/13/2024] [Indexed: 12/28/2024] Open
Affiliation(s)
- Marvin R. Natowicz
- Pathology and Laboratory Medicine, Genomic Medicine, Neurological and Pediatrics Institutes, Cleveland Clinic, Cleveland, OH, United States
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
| | - Margaret L. Bauman
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, United States
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3
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Yoon JH, Lee H, Kwon D, Lee D, Lee S, Cho E, Kim J, Kim D. Integrative approach of omics and imaging data to discover new insights for understanding brain diseases. Brain Commun 2024; 6:fcae265. [PMID: 39165479 PMCID: PMC11334939 DOI: 10.1093/braincomms/fcae265] [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: 12/11/2023] [Revised: 06/03/2024] [Accepted: 08/07/2024] [Indexed: 08/22/2024] Open
Abstract
Treatments that can completely resolve brain diseases have yet to be discovered. Omics is a novel technology that allows researchers to understand the molecular pathways underlying brain diseases. Multiple omics, including genomics, transcriptomics and proteomics, and brain imaging technologies, such as MRI, PET and EEG, have contributed to brain disease-related therapeutic target detection. However, new treatment discovery remains challenging. We focused on establishing brain multi-molecular maps using an integrative approach of omics and imaging to provide insights into brain disease diagnosis and treatment. This approach requires precise data collection using omics and imaging technologies, data processing and normalization. Incorporating a brain molecular map with the advanced technologies through artificial intelligence will help establish a system for brain disease diagnosis and treatment through regulation at the molecular level.
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Affiliation(s)
- Jong Hyuk Yoon
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Hagyeong Lee
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Dayoung Kwon
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Dongha Lee
- Cognitive Science Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Seulah Lee
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Eunji Cho
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Jaehoon Kim
- Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea
| | - Dayea Kim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea
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4
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Al-Beltagi M, Saeed NK, Bediwy AS, Elbeltagi R. Metabolomic changes in children with autism. World J Clin Pediatr 2024; 13:92737. [PMID: 38947988 PMCID: PMC11212761 DOI: 10.5409/wjcp.v13.i2.92737] [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: 02/04/2024] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Metabolomic profiling has emerged as a valuable tool for understanding the underlying metabolic dysregulations associated with ASD. AIM To comprehensively explore metabolomic changes in children with ASD, integrating findings from various research articles, reviews, systematic reviews, meta-analyses, case reports, editorials, and a book chapter. METHODS A systematic search was conducted in electronic databases, including PubMed, PubMed Central, Cochrane Library, Embase, Web of Science, CINAHL, Scopus, LISA, and NLM catalog up until January 2024. Inclusion criteria encompassed research articles (83), review articles (145), meta-analyses (6), systematic reviews (6), case reports (2), editorials (2), and a book chapter (1) related to metabolomic changes in children with ASD. Exclusion criteria were applied to ensure the relevance and quality of included studies. RESULTS The systematic review identified specific metabolites and metabolic pathways showing consistent differences in children with ASD compared to typically developing individuals. These metabolic biomarkers may serve as objective measures to support clinical assessments, improve diagnostic accuracy, and inform personalized treatment approaches. Metabolomic profiling also offers insights into the metabolic alterations associated with comorbid conditions commonly observed in individuals with ASD. CONCLUSION Integration of metabolomic changes in children with ASD holds promise for enhancing diagnostic accuracy, guiding personalized treatment approaches, monitoring treatment response, and improving outcomes. Further research is needed to validate findings, establish standardized protocols, and overcome technical challenges in metabolomic analysis. By advancing our understanding of metabolic dysregulations in ASD, clinicians can improve the lives of affected individuals and their families.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Tanta 31511, Alghrabia, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
- Department of Pediatric, University Medical Center, Dr. Sulaiman Al Habib Medical Group, Manama, Bahrain, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Bahrain, Busaiteen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Tanta 31527, Alghrabia, Egypt
- Department of Chest Disease, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
- Department of Chest Disease, University Medical Center, Dr. Sulaiman Al Habib Medical Group, Manama, Manama 26671, Bahrain
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland - Bahrain, Busiateen 15503, Muharraq, Bahrain
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5
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Nisar S, Haris M. Neuroimaging genetics approaches to identify new biomarkers for the early diagnosis of autism spectrum disorder. Mol Psychiatry 2023; 28:4995-5008. [PMID: 37069342 PMCID: PMC11041805 DOI: 10.1038/s41380-023-02060-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/19/2023]
Abstract
Autism-spectrum disorders (ASDs) are developmental disabilities that manifest in early childhood and are characterized by qualitative abnormalities in social behaviors, communication skills, and restrictive or repetitive behaviors. To explore the neurobiological mechanisms in ASD, extensive research has been done to identify potential diagnostic biomarkers through a neuroimaging genetics approach. Neuroimaging genetics helps to identify ASD-risk genes that contribute to structural and functional variations in brain circuitry and validate biological changes by elucidating the mechanisms and pathways that confer genetic risk. Integrating artificial intelligence models with neuroimaging data lays the groundwork for accurate diagnosis and facilitates the identification of early diagnostic biomarkers for ASD. This review discusses the significance of neuroimaging genetics approaches to gaining a better understanding of the perturbed neurochemical system and molecular pathways in ASD and how these approaches can detect structural, functional, and metabolic changes and lead to the discovery of novel biomarkers for the early diagnosis of ASD.
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Affiliation(s)
- Sabah Nisar
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
- Department of Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar.
- Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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6
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Martín-Hernández D, Muñoz-López M, Tendilla-Beltrán H, Caso JR, García-Bueno B, Menchén L, Leza JC. Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm? Int J Mol Sci 2023; 24:12634. [PMID: 37628815 PMCID: PMC10454107 DOI: 10.3390/ijms241612634] [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: 07/27/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Over the past few decades, extensive research has shed light on immune alterations and the significance of dysfunctional biological barriers in psychiatric disorders. The leaky gut phenomenon, intimately linked to the integrity of both brain and intestinal barriers, may play a crucial role in the origin of peripheral and central inflammation in these pathologies. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates both the immune response and the permeability of biological barriers. Notably, S1P-based drugs, such as fingolimod and ozanimod, have received approval for treating multiple sclerosis, an autoimmune disease of the central nervous system (CNS), and ulcerative colitis, an inflammatory condition of the colon, respectively. Although the precise mechanisms of action are still under investigation, the effectiveness of S1P-based drugs in treating these pathologies sparks a debate on extending their use in psychiatry. This comprehensive review aims to delve into the molecular mechanisms through which S1P modulates the immune system and brain/intestinal barrier functions. Furthermore, it will specifically focus on psychiatric diseases, with the primary objective of uncovering the potential of innovative therapies based on S1P signaling.
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Affiliation(s)
- David Martín-Hernández
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Marina Muñoz-López
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Hiram Tendilla-Beltrán
- Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla (BUAP), 72570 Puebla, Mexico;
| | - Javier R. Caso
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Borja García-Bueno
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Departamento de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain;
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (CIBEREHD, ISCIII), 28029 Madrid, Spain
| | - Juan C. Leza
- Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Hospital 12 de Octubre (i+12), Instituto Universitario de Investigación en Neuroquímica (IUIN), 28040 Madrid, Spain; (M.M.-L.); (J.R.C.); (B.G.-B.); (J.C.L.)
- Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM, ISCIII), 28029 Madrid, Spain
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Pretzsch CM, Ecker C. Structural neuroimaging phenotypes and associated molecular and genomic underpinnings in autism: a review. Front Neurosci 2023; 17:1172779. [PMID: 37457001 PMCID: PMC10347684 DOI: 10.3389/fnins.2023.1172779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023] Open
Abstract
Autism has been associated with differences in the developmental trajectories of multiple neuroanatomical features, including cortical thickness, surface area, cortical volume, measures of gyrification, and the gray-white matter tissue contrast. These neuroimaging features have been proposed as intermediate phenotypes on the gradient from genomic variation to behavioral symptoms. Hence, examining what these proxy markers represent, i.e., disentangling their associated molecular and genomic underpinnings, could provide crucial insights into the etiology and pathophysiology of autism. In line with this, an increasing number of studies are exploring the association between neuroanatomical, cellular/molecular, and (epi)genetic variation in autism, both indirectly and directly in vivo and across age. In this review, we aim to summarize the existing literature in autism (and neurotypicals) to chart a putative pathway from (i) imaging-derived neuroanatomical cortical phenotypes to (ii) underlying (neuropathological) biological processes, and (iii) associated genomic variation.
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Affiliation(s)
- Charlotte M. Pretzsch
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
| | - Christine Ecker
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
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8
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Boccazzi M, Raffaele S, Zanettin T, Abbracchio MP, Fumagalli M. Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors. Biomolecules 2023; 13:biom13050856. [PMID: 37238724 DOI: 10.3390/biom13050856] [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: 04/03/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
With the umbrella term 'neurodevelopmental disorders' (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions.
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Affiliation(s)
- Marta Boccazzi
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmaceutical Sciences, Università Degli Studi di Milano, 20133 Milan, Italy
| | - Stefano Raffaele
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, 20133 Milan, Italy
| | - Thomas Zanettin
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, 20133 Milan, Italy
| | - Maria P Abbracchio
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmaceutical Sciences, Università Degli Studi di Milano, 20133 Milan, Italy
| | - Marta Fumagalli
- Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, 20133 Milan, Italy
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9
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Kolvatzis C, Tsakiridis I, Kalogiannidis IA, Tsakoumaki F, Kyrkou C, Dagklis T, Daniilidis A, Michaelidou AM, Athanasiadis A. Utilizing Amniotic Fluid Metabolomics to Monitor Fetal Well-Being: A Narrative Review of the Literature. Cureus 2023; 15:e36986. [PMID: 37139280 PMCID: PMC10150141 DOI: 10.7759/cureus.36986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2023] [Indexed: 04/03/2023] Open
Abstract
Fetal and perinatal periods are critical phases for long-term development. Early diagnosis of maternal complications is challenging due to the great complexity of these conditions. In recent years, amniotic fluid has risen in a prominent position in the latest efforts to describe and characterize prenatal development. Amniotic fluid may provide real-time information on fetal development and metabolism throughout pregnancy as substances from the placenta, fetal skin, lungs, gastric fluid, and urine are transferred between the mother and the fetus. Applying metabolomics to monitor fetal well-being, in such a context, could help in the understanding, diagnosis, and treatment of these conditions and is a promising area of research. This review shines a spotlight on recent amniotic fluid metabolomics studies and their methods as an interesting tool for the assessment of many conditions and the identification of biomarkers. Platforms in use, such as proton nuclear magnetic resonance (1H NMR) and ultra-high-performance liquid chromatography (UHPLC), have different merits, and a combinatorial approach could be valuable. Metabolomics may also be used in the quest for habitual diet-induced metabolic signals in amniotic fluid. Finally, analysis of amniotic fluid can provide information on exposure to exogenous substances by detecting the exact levels of metabolites carried to the fetus and associated metabolic effects.
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10
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Dai S, Lin J, Hou Y, Luo X, Shen Y, Ou J. Purine signaling pathway dysfunction in autism spectrum disorders: Evidence from multiple omics data. Front Mol Neurosci 2023; 16:1089871. [PMID: 36818658 PMCID: PMC9935591 DOI: 10.3389/fnmol.2023.1089871] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Introduction Previous studies have suggested that the dysregulation of purine metabolism may be associated with autism spectrum disorder (ASD). Here, we adopted metabolomics and transcriptomics to verify and explore the underlying molecular mechanism of purine metabolism dysfunction in ASD and identify potential biomarkers within the purine metabolism pathway. Methods Ultra-high-performance liquid chromatography-mass spectrometry was used to obtain the plasma metabolic profiles of 12 patients with ASD and 12 typically developing (TD) children. RNA sequencing was used to screen differentially expressed genes related to the purine metabolic pathway and purine receptor-coding genes in 24 children with ASD and 21 healthy controls. Finally, serum uric acid levels were compared in 80 patients with ASD and 174 TD children to validate the omics results. Results A total of 66 identified metabolites showed significant between-group differences. Network analysis showed that purine metabolism was the most strongly enriched. Uric acid was one of the most highlighted nodes within the network. The transcriptomic study revealed significant differential expression of three purine metabolism-related genes (adenosine deaminase, adenylosuccinate lyase, and bifunctional enzyme neoformans 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/inosine monophosphate (IMP) cyclohydrolase) (p < 0.01) and five purinergic receptor genes (P2X7, P2Y2, P2Y6, P2Y8, and P2Y10) (p < 0.05). In the validation sample, there was a significant difference in serum uric acid levels between the two groups (p < 0.001), and the area under the curve for uric acid was 0.812 (sensitivity, 82.5%; specificity, 63.8%). Discussion Patients with ASD had dysfunctional purine metabolic pathways, and blood uric acid may be a potential biomarker for ASD.
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11
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Breen MS, Fan X, Levy T, Pollak RM, Collins B, Osman A, Tocheva AS, Sahin M, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Kolevzon A, Buxbaum JD. Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome. HGG ADVANCES 2023; 4:100145. [PMID: 36276299 PMCID: PMC9579712 DOI: 10.1016/j.xhgg.2022.100145] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 09/23/2022] [Indexed: 11/25/2022] Open
Abstract
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Phenotypic differences have been reported between PMS participants carrying small "class I" mutations and large "class II" mutations; however, the molecular perturbations underlying these divergent phenotypes remain obscure. Using peripheral blood transcriptome and serum metabolome profiling, we examined the molecular perturbations in the peripheral circulation associated with a full spectrum of PMS genotypes spanning class I (n = 37) and class II mutations (n = 39). Transcriptomic data revealed 52 genes with blood expression profiles that tightly scale with 22q.13.3 deletion size. Furthermore, we uncover 208 underexpressed genes in PMS participants with class II mutations, which were unchanged in class I mutations. These genes were not linked to 22q13.3 and were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions, and cytotoxic natural killer (NK) immune cell signatures. In silico predictions estimated a reduction in CD56+ CD16- NK cell proportions in class II mutations, which was validated by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered in PMS participants with class II mutations and confirmed a general reduction in sphingolipid metabolism. Collectively, these results provide new evidence linking PMS participants carrying class II mutations with decreased expression of cytotoxic cell signatures, reduced relative proportions of NK cells, and lower sphingolipid metabolism. These findings highlight alternative avenues for therapeutic development and offer new mechanistic insights supporting genotype-to-phenotype associations in PMS.
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Affiliation(s)
- Michael S Breen
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Xuanjia Fan
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tess Levy
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rebecca M Pollak
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brett Collins
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aya Osman
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anna S Tocheva
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mustafa Sahin
- Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Rosamund Stone Zander Translational Neuroscience Center and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Elizabeth Berry-Kravis
- Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA.,Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
| | - Latha Soorya
- Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA
| | - Audrey Thurm
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Craig M Powell
- Department of Neurobiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.,Civitan International Research Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Jonathan A Bernstein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Alexander Kolevzon
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joseph D Buxbaum
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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12
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Cntnap2-dependent molecular networks in autism spectrum disorder revealed through an integrative multi-omics analysis. Mol Psychiatry 2023; 28:810-821. [PMID: 36253443 PMCID: PMC9908544 DOI: 10.1038/s41380-022-01822-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 09/15/2022] [Accepted: 09/26/2022] [Indexed: 12/28/2022]
Abstract
Autism spectrum disorder (ASD) is a major neurodevelopmental disorder in which patients present with core symptoms of social communication impairment, restricted interest, and repetitive behaviors. Although various studies have been performed to identify ASD-related mechanisms, ASD pathology is still poorly understood. CNTNAP2 genetic variants have been found that represent ASD genetic risk factors, and disruption of Cntnap2 expression has been associated with ASD phenotypes in mice. In this study, we performed an integrative multi-omics analysis by combining quantitative proteometabolomic data obtained with Cntnap2 knockout (KO) mice with multi-omics data obtained from ASD patients and forebrain organoids to elucidate Cntnap2-dependent molecular networks in ASD. To this end, a mass spectrometry-based proteometabolomic analysis of the medial prefrontal cortex in Cntnap2 KO mice led to the identification of Cntnap2-associated molecular features, and these features were assessed in combination with multi-omics data obtained on the prefrontal cortex in ASD patients to identify bona fide ASD cellular processes. Furthermore, a reanalysis of single-cell RNA sequencing data obtained from forebrain organoids derived from patients with CNTNAP2-associated ASD revealed that the aforementioned identified ASD processes were mainly linked to excitatory neurons. On the basis of these data, we constructed Cntnap2-associated ASD network models showing mitochondrial dysfunction, axonal impairment, and synaptic activity. Our results may shed light on the Cntnap2-dependent molecular networks in ASD.
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13
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Murtaza N, Cheng AA, Brown CO, Meka DP, Hong S, Uy JA, El-Hajjar J, Pipko N, Unda BK, Schwanke B, Xing S, Thiruvahindrapuram B, Engchuan W, Trost B, Deneault E, Calderon de Anda F, Doble BW, Ellis J, Anagnostou E, Bader GD, Scherer SW, Lu Y, Singh KK. Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies. Cell Rep 2022; 41:111678. [DOI: 10.1016/j.celrep.2022.111678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 08/16/2022] [Accepted: 10/25/2022] [Indexed: 11/23/2022] Open
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14
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Liberti J, Kay T, Quinn A, Kesner L, Frank ET, Cabirol A, Richardson TO, Engel P, Keller L. The gut microbiota affects the social network of honeybees. Nat Ecol Evol 2022; 6:1471-1479. [PMID: 35995848 PMCID: PMC7613669 DOI: 10.1038/s41559-022-01840-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/27/2022] [Indexed: 01/14/2023]
Abstract
The gut microbiota influences animal neurodevelopment and behaviour but has not previously been documented to affect group-level properties of social organisms. Here, we use honeybees to probe the effect of the gut microbiota on host social behaviour. We found that the microbiota increased the rate and specialization of head-to-head interactions between bees. Microbiota colonization was associated with higher abundances of one-third of the metabolites detected in the brain, including amino acids with roles in synaptic transmission and brain energetic function. Some of these metabolites were significant predictors of the number of social interactions. Microbiota colonization also affected brain transcriptional processes related to amino acid metabolism and epigenetic modifications in a brain region involved in sensory perception. These results demonstrate that the gut microbiota modulates the emergent colony social network of honeybees and suggest changes in chromatin accessibility and amino acid biosynthesis as underlying processes.
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Affiliation(s)
- Joanito Liberti
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland.
- Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland.
| | - Tomas Kay
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Andrew Quinn
- Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland
| | - Lucie Kesner
- Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland
| | - Erik T Frank
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
- Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany
| | - Amélie Cabirol
- Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland
| | - Thomas O Richardson
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Philipp Engel
- Department of Fundamental Microbiology, University of Lausanne, Lausanne, Switzerland.
| | - Laurent Keller
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland.
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15
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Tissue-wide cell-specific proteogenomic modeling reveals novel candidate risk genes in autism spectrum disorders. NPJ Syst Biol Appl 2022; 8:31. [PMID: 36068227 PMCID: PMC9448731 DOI: 10.1038/s41540-022-00243-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 08/05/2022] [Indexed: 11/08/2022] Open
Abstract
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental diseases characterized with repetitive behavioral patterns and communication disabilities. Using a systems biology method called MAPSD (Markov Affinity-based Proteogenomic Signal Diffusion) for joint modeling of proteome dynamics and a wide array of omics datasets, we identified a list of candidate ASD risk genes. Leveraging the collected biological signals as well as a large-scale protein-protein interaction network adjusted based on single cell resolution proteome properties in four brain regions, we observed an agreement between the known and the newly identified candidate genes that are spatially enriched in neuronal cells within cerebral cortex at the protein level. Moreover, we created a detailed subcellular localization enrichment map of the known and the identified genes across 32 micro-domains and showed that neuronal cells and neuropils share the largest fraction of signal enrichment in cerebral cortex. Notably, we showed that the identified genes are among the transcriptional biomarkers of inhibitory and excitatory neurons in human frontal cortex. Intersecting the identified genes with a single cell RNA-seq data on ASD brains further evidenced that 20 candidate genes, including GRIK1, EMX2, STXBP6, and KCNJ3 are disrupted in distinct cell-types. Moreover, we showed that ASD risk genes are predominantly distributed in certain human interactome modules, and that the identified genes may act as the regulator for some of the known ASD loci. In summary, our study demonstrated how tissue-wide cell-specific proteogenomic modeling can reveal candidate genes for brain disorders that can be supported by convergent lines of evidence.
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16
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Choi M, Ko SY, Seo JY, Kim DG, Lee H, Chung H, Son H. Autistic-like social deficits in hippocampal MeCP2 knockdown rat models are rescued by ketamine. BMB Rep 2022. [PMID: 35410641 PMCID: PMC9152577 DOI: 10.5483/bmbrep.2022.55.5.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Autism or autism spectrum disorder (ASD) is a behavioral syndrome characterized by persistent deficits in social interaction, and repetitive patterns of behavior, interests, or activities. The gene encoding Methyl-CpG binding protein 2 (MeCP2) is one of a few exceptional genes of established causal effect in ASD. Although genetically engineered mice studies may shed light on how MeCP2 loss affects synaptic activity patterns across the whole brain, such studies are not considered practical in ASD patients due to the overall level of impairment, and are technically challenging in mice. For the first time, we show that hippo-campal MeCP2 knockdown produces behavioral abnormalities associated with autism-like traits in rats, providing a new strategy to investigate the efficacy of therapeutics in ASD. Ketamine, an N-Methyl-D-aspartate (NMDA) blocker, has been proposed as a possible treatment for autism. Using the MeCP2 knockdown rats in conjunction with a rat model of valproic acid (VPA)-induced ASD, we examined gene expression and ASD behaviors upon ketamine treatment. We report that the core symptoms of autism in MeCP2 knockdown rats with social impairment recovered dramatically following a single treatment with ketamine.
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Affiliation(s)
- Miyeon Choi
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
| | - Seung Yeon Ko
- Hanyang Biomedical Research Institute, Hanyang University, Seoul 04763, Korea
| | - Jee Young Seo
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Do Gyeong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Huiju Lee
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Heekyoung Chung
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Hyeon Son
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
- Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul 04763, Korea
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17
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Shen L, Zhang H, Lin J, Gao Y, Chen M, Khan NU, Tang X, Hong Q, Feng C, Zhao Y, Cao X. A Combined Proteomics and Metabolomics Profiling to Investigate the Genetic Heterogeneity of Autistic Children. Mol Neurobiol 2022; 59:3529-3545. [PMID: 35348996 DOI: 10.1007/s12035-022-02801-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 03/16/2022] [Indexed: 11/30/2022]
Abstract
Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces significant challenges due to the existence of heterogeneity. In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out. The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, peripheral blood mononuclear cells, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focuses on several common and previously reported mechanisms of ASD. The biomarkers for ASD diagnosis could be found by taking differentially expressed proteins and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.
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Affiliation(s)
- Liming Shen
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China
| | - Huajie Zhang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China.,Brain Disease and Big Data Research Institute, Shenzhen University, Shenzhen, 518071, People's Republic of China
| | - Jing Lin
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China.,Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, People's Republic of China
| | - Yan Gao
- Maternal and Child Health Hospital of Baoan, Shenzhen, 518100, People's Republic of China
| | - Margy Chen
- Department of Psychology, Emory University, Atlanta, GA, 30322, USA
| | - Naseer Ullah Khan
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China
| | - Xiaoxiao Tang
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China
| | - Qi Hong
- Maternal and Child Health Hospital of Baoan, Shenzhen, 518100, People's Republic of China
| | - Chengyun Feng
- Maternal and Child Health Hospital of Baoan, Shenzhen, 518100, People's Republic of China
| | - Yuxi Zhao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China.
| | - Xueshan Cao
- College of Life Science and Oceanography, Shenzhen University, Shenzhen, 518071, People's Republic of China.
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18
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Mohammad FK, Palukuri MV, Shivakumar S, Rengaswamy R, Sahoo S. A Computational Framework for Studying Gut-Brain Axis in Autism Spectrum Disorder. Front Physiol 2022; 13:760753. [PMID: 35330929 PMCID: PMC8940246 DOI: 10.3389/fphys.2022.760753] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 01/17/2022] [Indexed: 12/28/2022] Open
Abstract
Introduction The integrity of the intestinal epithelium is crucial for human health and is harmed in autism spectrum disorder (ASD). An aberrant gut microbial composition resulting in gut-derived metabolic toxins was found to damage the intestinal epithelium, jeopardizing tissue integrity. These toxins further reach the brain via the gut-brain axis, disrupting the normal function of the brain. A mechanistic understanding of metabolic disturbances in the brain and gut is essential to design effective therapeutics and early intervention to block disease progression. Herein, we present a novel computational framework integrating constraint based tissue specific metabolic (CBM) model and whole-body physiological pharmacokinetics (PBPK) modeling for ASD. Furthermore, the role of gut microbiota, diet, and oxidative stress is analyzed in ASD. Methods A representative gut model capturing host-bacteria and bacteria-bacteria interaction was developed using CBM techniques and patient data. Simultaneously, a PBPK model of toxin metabolism was assembled, incorporating multi-scale metabolic information. Furthermore, dynamic flux balance analysis was performed to integrate CBM and PBPK. The effectiveness of a probiotic and dietary intervention to improve autism symptoms was tested on the integrated model. Results The model accurately highlighted critical metabolic pathways of the gut and brain that are associated with ASD. These include central carbon, nucleotide, and vitamin metabolism in the host gut, and mitochondrial energy and amino acid metabolisms in the brain. The proposed dietary intervention revealed that a high-fiber diet is more effective than a western diet in reducing toxins produced inside the gut. The addition of probiotic bacteria Lactobacillus acidophilus, Bifidobacterium longum longum, Akkermansia muciniphila, and Prevotella ruminicola to the diet restores gut microbiota balance, thereby lowering oxidative stress in the gut and brain. Conclusion The proposed computational framework is novel in its applicability, as demonstrated by the determination of the whole-body distribution of ROS toxins and metabolic association in ASD. In addition, it emphasized the potential for developing novel therapeutic strategies to alleviate autism symptoms. Notably, the presented integrated model validates the importance of combining PBPK modeling with COBRA -specific tissue details for understanding disease pathogenesis.
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Affiliation(s)
- Faiz Khan Mohammad
- Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, India
| | - Meghana Venkata Palukuri
- Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, India.,Initiative for Biological Systems Engineering, Indian Institute of Technology Madras, Chennai, India
| | - Shruti Shivakumar
- Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, India.,Initiative for Biological Systems Engineering, Indian Institute of Technology Madras, Chennai, India
| | - Raghunathan Rengaswamy
- Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, India.,Initiative for Biological Systems Engineering, Indian Institute of Technology Madras, Chennai, India
| | - Swagatika Sahoo
- Department of Chemical Engineering, Indian Institute of Technology Madras, Chennai, India.,Initiative for Biological Systems Engineering, Indian Institute of Technology Madras, Chennai, India
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19
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Yehia L, Ni Y, Sadler T, Frazier TW, Eng C. Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations. NPJ Genom Med 2022; 7:16. [PMID: 35241692 PMCID: PMC8894426 DOI: 10.1038/s41525-022-00289-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 12/16/2021] [Indexed: 11/09/2022] Open
Abstract
PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, has been associated with organ-specific cancers and autism spectrum disorder (ASD) and/or developmental delay (DD). Predicting precise clinical phenotypes in any one PHTS individual remains impossible. We conducted an untargeted metabolomics study on an age- and sex-matched series of PHTS individuals with ASD/DD, cancer, or both phenotypes. Using agnostic metabolomic-analyses from patient-derived lymphoblastoid cells and their spent media, we found 52 differentially abundant individual metabolites, 69 cell/media metabolite ratios, and 327 pair-wise metabotype (shared metabolic phenotype) ratios clearly distinguishing PHTS individuals based on phenotype. Network analysis based on significant metabolites pointed to hubs converging on PTEN-related insulin, MAPK, AMPK, and mTOR signaling cascades. Internal cross-validation of significant metabolites showed optimal overall accuracy in distinguishing PHTS individuals with ASD/DD versus those with cancer. Such metabolomic markers may enable more accurate risk predictions and prevention in individual PHTS patients at highest risk.
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Affiliation(s)
- Lamis Yehia
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ying Ni
- Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Tammy Sadler
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Thomas W Frazier
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Autism Speaks, Cleveland, OH, USA.,Department of Psychology, John Carroll University, University Heights, OH, USA
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. .,Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. .,Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA. .,Germline High Risk Cancer Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
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20
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Park G, Jeon SJ, Ko IO, Park JH, Lee KC, Kim MS, Shin CY, Kim H, Lee YS. Decreased in vivo glutamate/GABA ratio correlates with the social behavior deficit in a mouse model of autism spectrum disorder. Mol Brain 2022; 15:19. [PMID: 35183218 PMCID: PMC8858545 DOI: 10.1186/s13041-022-00904-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/08/2022] [Indexed: 12/29/2022] Open
Abstract
To diagnose autism spectrum disorder (ASD), researchers have sought biomarkers whose alterations correlate with the susceptibility to ASD. However, biomarkers closely related to the pathophysiology of ASD are lacking. Even though excitation/inhibition (E/I) imbalance has been suggested as an underlying mechanism of ASD, few studies have investigated the actual ratio of glutamate (Glu) to γ-aminobutyric acid (GABA) concentration in vivo. Moreover, there are controversies in the directions of E/I ratio alterations even in extensively studied ASD animal models. Here, using proton magnetic resonance spectroscopy (1H-MRS) at 9.4T, we found significant differences in the levels of different metabolites or their ratios in the prefrontal cortex and hippocampus of Cntnap2−/− mice compared to their wild-type littermates. The Glu/GABA ratio, N-acetylaspartate (NAA)/total creatine (tCr) ratio, and tCr level in the prefrontal cortex were significantly different in Cntnap2−/− mice compared to those in wild-type mice, and they significantly correlated with the sociability of mice. Moreover, receiver operating characteristic (ROC) analyses indicated high specificity and selectivity of these metabolites in discriminating genotypes. These results suggest that the lowered Glu/GABA ratio in the prefrontal cortex along with the changes in the other metabolites might contribute to the social behavior deficit in Cntnap2−/− mice. Our results also demonstrate the utility of 1H-MRS in investigating the underlying mechanisms or the diagnosis of ASD.
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21
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Applications of Unsupervised Machine Learning in Autism Spectrum Disorder Research: a Review. REVIEW JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS 2022. [DOI: 10.1007/s40489-021-00299-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
AbstractLarge amounts of autism spectrum disorder (ASD) data is created through hospitals, therapy centers, and mobile applications; however, much of this rich data does not have pre-existing classes or labels. Large amounts of data—both genetic and behavioral—that are collected as part of scientific studies or a part of treatment can provide a deeper, more nuanced insight into both diagnosis and treatment of ASD. This paper reviews 43 papers using unsupervised machine learning in ASD, including k-means clustering, hierarchical clustering, model-based clustering, and self-organizing maps. The aim of this review is to provide a survey of the current uses of unsupervised machine learning in ASD research and provide insight into the types of questions being answered with these methods.
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22
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Kim HY, Lee YJ, Kim SJ, Lee JD, Kim S, Ko MJ, Kim JW, Shin CY, Kim KB. Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2022; 85:1-13. [PMID: 34445937 DOI: 10.1080/15287394.2021.1967821] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Prenatal exposure to valproic acid (VPA) has been implicated in the manifestation of autism spectrum disorder (ASD)-like behavioral and functional changes both in human and rodents including mice and rats. The objective of this study was to determine metabolomics profiling and biomarkers related to VPA-induced symptoms resembling ASD using proton nuclear magnetic resonance (1H-NMR) spectral data. VPA was administered to pregnant rats at gestation day 12.5 and effects measured subsequently in male 4-week-old offspring pups. The sociability of VPA-treated animals was significantly diminished and exhibited ASD-like behavior as evidenced by reduction of social adaptation disorder and lack of social interactions. To find biomarkers related to ASD, the following were collected prefrontal brain cortices, urine bladder and blood samples directly from heart puncture. In all samples, principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) displayed significant clustering pattern differences between control and treated groups. Valine, taurine, myo-inositol, 3-hydroxybutyrate and 1,3-dihydroxyacetone were significantly decreased in brain cortices in treated rats. Serum metabolites of glucose, creatine phosphate, lactate, glutamine and threonine were significantly increased in VPA-administered animals. Urinary metabolites of pimelate, 3-hydroxyisovalerate and valerate were significantly reduced in VPA-treated rat, whereas galactose and galactonate levels were elevated. Various metabolites were associated with mitochondrial dysfunction metabolism and central nervous system disorders. Data demonstrated that VPA-induced alterations in endogenous metabolites of serum, urine, and brain cortex which might prove useful as biomarkers for symptoms resembling ASD as a model of this disorder.
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Affiliation(s)
- Hyang Yeon Kim
- College of Pharmacy, Dankook University, Cheonan, Chungnam, Republic of Korea
- Center for Human Risk Assessment, Dankook University, Cheonan, Chungnam Republic of Korea
| | - Yong-Jae Lee
- College of Pharmacy, Dankook University, Cheonan, Chungnam, Republic of Korea
| | - Sun Jae Kim
- College of Pharmacy, Dankook University, Cheonan, Chungnam, Republic of Korea
| | - Jung Dae Lee
- College of Pharmacy, Dankook University, Cheonan, Chungnam, Republic of Korea
- Center for Human Risk Assessment, Dankook University, Cheonan, Chungnam Republic of Korea
| | - Suhkmann Kim
- Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan Republic of Korea
| | - Mee Jung Ko
- Department Of Neuroscience, School Of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Ji-Woon Kim
- Department Of Neuroscience, School Of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Chan Young Shin
- Department Of Neuroscience, School Of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Kyu-Bong Kim
- College of Pharmacy, Dankook University, Cheonan, Chungnam, Republic of Korea
- Center for Human Risk Assessment, Dankook University, Cheonan, Chungnam Republic of Korea
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23
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Abstract
During evolution, the cerebral cortex advances by increasing in surface and the introduction of new cytoarchitectonic areas among which the prefrontal cortex (PFC) is considered to be the substrate of highest cognitive functions. Although neurons of the PFC are generated before birth, the differentiation of its neurons and development of synaptic connections in humans extend to the 3rd decade of life. During this period, synapses as well as neurotransmitter systems including their receptors and transporters, are initially overproduced followed by selective elimination. Advanced methods applied to human and animal models, enable investigation of the cellular mechanisms and role of specific genes, non-coding regulatory elements and signaling molecules in control of prefrontal neuronal production and phenotypic fate, as well as neuronal migration to establish layering of the PFC. Likewise, various genetic approaches in combination with functional assays and immunohistochemical and imaging methods reveal roles of neurotransmitter systems during maturation of the PFC. Disruption, or even a slight slowing of the rate of neuronal production, migration and synaptogenesis by genetic or environmental factors, can induce gross as well as subtle changes that eventually can lead to cognitive impairment. An understanding of the development and evolution of the PFC provide insight into the pathogenesis and treatment of congenital neuropsychiatric diseases as well as idiopathic developmental disorders that cause intellectual disabilities.
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Affiliation(s)
- Sharon M Kolk
- Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, Nijmegen, The Netherlands.
| | - Pasko Rakic
- Department of Neuroscience and Kavli Institute for Neuroscience, Yale University, New Haven, Connecticut, USA.
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24
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Rong P, Fu Q, Zhang X, Liu H, Zhao S, Song X, Gao P, Ma R. A bibliometrics analysis and visualization of autism spectrum disorder. Front Psychiatry 2022; 13:884600. [PMID: 35923445 PMCID: PMC9339633 DOI: 10.3389/fpsyt.2022.884600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/28/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The prevalence of autism spectrum disorder (ASD) increased rapidly in the last 20 years. Although related research has developed rapidly, little is known about its etiology, diagnostic marker, or drug treatment, which forces researchers to review and summarize its development process and look for the future development direction. METHODS We used bibliometrics to analyze papers of ASD in the Web of Science from 1998 to 2021, to draw the network of authors, institutions, countries, and keywords in the ASD field, and visualize the results. RESULTS A total of 40,597 papers were included with a continually increasing trend. It turns out that the research on ASD is mainly concentrated in universities. The United States has the largest number of ASD studies, followed by England and Canada. The quality of papers related to ASD is generally high, which shows that ASD research has become a hot spot of scientific research. The keywords of ASD etiology and diagnostic markers can be classified into at least 7 aspects. The detection of keywords shows that ASD research is mostly based on its subtypes, takes children as the study population, focuses on neurodevelopmental imaging or genetics, and pays attention to individual differences. And ASD research has changed greatly under the impact of Corona Virus Disease 2019 in the past 2 years. CONCLUSION We consider the future development direction should be based on the improvement of case identification, accurate clinical phenotype, large-scale cohort study, the discovery of ASD etiology and diagnostic markers, drug randomized controlled trials, and telehealth.
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Affiliation(s)
- Ping Rong
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Qianfang Fu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xilian Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hui Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shuyi Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xinxin Song
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Puxing Gao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Rong Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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25
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Dean DD, Agarwal S, Muthuswamy S, Asim A. Brain exosomes as minuscule information hub for Autism Spectrum Disorder. Expert Rev Mol Diagn 2021; 21:1323-1331. [PMID: 34720032 DOI: 10.1080/14737159.2021.2000395] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Autism spectrum disorder (ASD) is a neurodevelopmental disorder initiating in the first three years of life. Early initiation of management therapies can significantly improve the health and quality of life of ASD subjects. Thus, indicating the need for suitable biomarkers for the early identification of ASD. Various biological domains were investigated in the quest for reliable biomarkers. However, most biomarkers are in the preliminary stage, and clinical validation is yet to be defined. Exosome based research gained momentum in various Central Nervous System disorders for biomarker identification. However, the utility and prospect of exosomes in ASD is still underexplored. AREAS COVERED In the present review, we summarized the biomarker discovery current status and the future of brain-specific exosomes in understanding pathophysiology and its potential as a biomarker. The studies reviewed herein were identified via systematic search (dated: June 2021) of PubMed using variations related to autism (ASD OR autism OR Autism spectrum disorder) AND exosomes AND/OR biomarkers. EXPERT OPINION As exosomess are highly relevant in brain disorders like ASD, direct access to brain tissue for molecular assessment is ethically impossible. Thus investigating the brain-derived exosomes would undoubtedly answer many unsolved aspects of the pathogenesis and provide reliable biomarkers.
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Affiliation(s)
- Deepika Delsa Dean
- Deptartment of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (Sgpgims), Lucknow, India
| | - Sarita Agarwal
- Deptartment of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (Sgpgims), Lucknow, India
| | | | - Ambreen Asim
- Deptartment of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (Sgpgims), Lucknow, India
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26
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Peralta-Marzal LN, Prince N, Bajic D, Roussin L, Naudon L, Rabot S, Garssen J, Kraneveld AD, Perez-Pardo P. The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders. Int J Mol Sci 2021; 22:10052. [PMID: 34576216 PMCID: PMC8470471 DOI: 10.3390/ijms221810052] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders characterised by behavioural impairment and deficiencies in social interaction and communication. A recent study estimated that 1 in 89 children have developed some form of ASD in European countries. Moreover, there is no specific treatment and since ASD is not a single clinical entity, the identification of molecular biomarkers for diagnosis remains challenging. Besides behavioural deficiencies, individuals with ASD often develop comorbid medical conditions including intestinal problems, which may reflect aberrations in the bidirectional communication between the brain and the gut. The impact of faecal microbial composition in brain development and behavioural functions has been repeatedly linked to ASD, as well as changes in the metabolic profile of individuals affected by ASD. Since metabolism is one of the major drivers of microbiome-host interactions, this review aims to report emerging literature showing shifts in gut microbiota metabolic function in ASD. Additionally, we discuss how these changes may be involved in and/or perpetuate ASD pathology. These valuable insights can help us to better comprehend ASD pathogenesis and may provide relevant biomarkers for improving diagnosis and identifying new therapeutic targets.
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Affiliation(s)
- Lucía N. Peralta-Marzal
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
| | - Naika Prince
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
| | - Djordje Bajic
- Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06511, USA;
- Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA
| | - Léa Roussin
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; (L.R.); (S.R.)
| | - Laurent Naudon
- CNRS, Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France;
| | - Sylvie Rabot
- Micalis Institute, INRAE, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; (L.R.); (S.R.)
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
- Danone Nutricia Research, 3584 CT Utrecht, The Netherlands
| | - Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
| | - Paula Perez-Pardo
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands; (N.P.); (J.G.); (A.D.K.)
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27
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Kulkarni AS, Huang L, Qian K. Material-assisted mass spectrometric analysis of low molecular weight compounds for biomedical applications. J Mater Chem B 2021; 9:3622-3639. [PMID: 33871513 DOI: 10.1039/d1tb00289a] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Low molecular weight compounds play an important role in encoding the current physiological state of an individual. Laser desorption/ionization mass spectrometry (LDI MS) offers high sensitivity with low cost for molecular detection, but it is not able to cover small molecules due to the drawbacks of the conventional matrix. Advanced materials are better alternatives, showing little background interference and high LDI efficiency. Herein, we first classify the current materials with a summary of compositions and structures. Matrix preparation protocols are then reviewed, to enhance the selectivity and reproducibility of MS data better. Finally, we highlight the biomedical applications of material-assisted LDI MS, at the tissue, bio-fluid, and cellular levels. We foresee that the advanced materials will bring far-reaching implications in LDI MS towards real-case applications, especially in clinical settings.
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Affiliation(s)
- Anuja Shreeram Kulkarni
- State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, P. R. China and School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China.
| | - Lin Huang
- Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, P. R. China.
| | - Kun Qian
- State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, P. R. China and School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China.
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28
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Stanton JE, Malijauskaite S, McGourty K, Grabrucker AM. The Metallome as a Link Between the "Omes" in Autism Spectrum Disorders. Front Mol Neurosci 2021; 14:695873. [PMID: 34290588 PMCID: PMC8289253 DOI: 10.3389/fnmol.2021.695873] [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: 04/22/2021] [Accepted: 06/14/2021] [Indexed: 12/26/2022] Open
Abstract
Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other "omes," which may together result in an individual's specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other "omes" are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other "omes" in the body in the context of "omics" studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.
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Affiliation(s)
- Janelle E Stanton
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Bernal Institute, University of Limerick, Limerick, Ireland
| | - Sigita Malijauskaite
- Bernal Institute, University of Limerick, Limerick, Ireland.,Department of Chemical Sciences, University of Limerick, Limerick, Ireland
| | - Kieran McGourty
- Bernal Institute, University of Limerick, Limerick, Ireland.,Department of Chemical Sciences, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
| | - Andreas M Grabrucker
- Department of Biological Sciences, University of Limerick, Limerick, Ireland.,Bernal Institute, University of Limerick, Limerick, Ireland.,Health Research Institute, University of Limerick, Limerick, Ireland
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29
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Evolutionary Changes in Pathways and Networks of Genes Expressed in the Brains of Humans and Macaques. J Mol Neurosci 2021; 71:1825-1837. [PMID: 34191269 DOI: 10.1007/s12031-021-01874-y] [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: 03/02/2021] [Accepted: 06/15/2021] [Indexed: 10/21/2022]
Abstract
As the key organ that separates humans from nonhuman primates, the brain has continuously evolved to adapt to environmental and climatic changes. Although humans share most genetic, molecular, and cellular features with other primates such as macaques, there are significant differences in the structure and function of the brain between humans and these species. Thus, exploring the differences between the brains of human and nonhuman primates in the context of evolution will provide insights into the development, functionality, and diseases of the human central nervous system (CNS). Since the genes involved in many aspects of the human brain are under common pressures of natural selection, their evolutionary features can be analyzed collectively at the pathway level. In this study, the molecular mechanisms underlying human brain capabilities were explored by comparing the evolution features of pathways enriched in genes expressed in the human brain and the macaque brain. We identified 31 pathways with differential evolutionary properties, including those related to neurological diseases, signal transduction, immunological response, and metabolic processes. By analyzing genes differentially expressed in brain regions or development stages between humans and macaques, 9 and 4 pathways with differential evolutionary properties were detected, respectively. We further performed crosstalk analysis on the pathways to obtain an intuitive correlation between the pathways, which is helpful in understanding the mechanisms of interaction between pathways. Our results provide on a comprehensive view of the evolutionary pathways of the human CNS and can serve as a reference for the study of human brain development.
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30
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Stepanova V, Moczulska KE, Vacano GN, Kurochkin I, Ju X, Riesenberg S, Macak D, Maricic T, Dombrowski L, Schörnig M, Anastassiadis K, Baker O, Naumann R, Khrameeva E, Vanushkina A, Stekolshchikova E, Egorova A, Tkachev A, Mazzarino R, Duval N, Zubkov D, Giavalisco P, Wilkinson TG, Patterson D, Khaitovich P, Pääbo S. Reduced purine biosynthesis in humans after their divergence from Neandertals. eLife 2021; 10:58741. [PMID: 33942714 PMCID: PMC8133780 DOI: 10.7554/elife.58741] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 05/02/2021] [Indexed: 12/02/2022] Open
Abstract
We analyze the metabolomes of humans, chimpanzees, and macaques in muscle, kidney and three different regions of the brain. Although several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans.
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Affiliation(s)
- Vita Stepanova
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation.,Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, Russian Federation
| | | | - Guido N Vacano
- The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
| | - Ilia Kurochkin
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
| | - Xiangchun Ju
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.,Okinawa Institute of Science and Technology, Onna-son, Japan
| | | | - Dominik Macak
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
| | - Tomislav Maricic
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
| | - Linda Dombrowski
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
| | - Maria Schörnig
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
| | - Konstantinos Anastassiadis
- Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technical University Dresden, Dresden, Germany
| | - Oliver Baker
- Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technical University Dresden, Dresden, Germany
| | - Ronald Naumann
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | | | - Anna Vanushkina
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
| | | | - Alina Egorova
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
| | - Anna Tkachev
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
| | - Randall Mazzarino
- The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
| | - Nathan Duval
- The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
| | - Dmitri Zubkov
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
| | | | - Terry G Wilkinson
- The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
| | - David Patterson
- The Eleanor Roosevelt Institute and Knoebel Institute for Healthy Aging, University of Denver, Denver, United States
| | - Philipp Khaitovich
- Skolkovo Institute for Science and Technology, Skolkovo, Russian Federation
| | - Svante Pääbo
- Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.,Okinawa Institute of Science and Technology, Onna-son, Japan
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31
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Kim JH, Yan Q, Uppal K, Cui X, Ling C, Walker DI, Heck JE, von Ehrenstein OS, Jones DP, Ritz B. Metabolomics analysis of maternal serum exposed to high air pollution during pregnancy and risk of autism spectrum disorder in offspring. ENVIRONMENTAL RESEARCH 2021; 196:110823. [PMID: 33548296 PMCID: PMC9059845 DOI: 10.1016/j.envres.2021.110823] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/27/2021] [Accepted: 01/27/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Previously, numerous epidemiologic studies reported an association between autism spectrum disorder (ASD) and exposure to air pollution during pregnancy. However, there have been no metabolomics studies investigating the impact of pregnancy pollution exposure to ASD risk in offspring. OBJECTIVES To identify differences in maternal metabolism that may reflect a biological response to exposure to high air pollution in pregnancies of offspring who later did or did not develop ASD. METHODS We obtained stored mid-pregnancy serum from 214 mothers who lived in California's Central Valley and experienced the highest levels of air pollution during early pregnancy. We estimated each woman's average traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter <2.5 μm) during the first trimester using the California Line Source Dispersion Model, version 4 (CALINE4). By utilizing liquid chromatography-high resolution mass spectrometry, we identified the metabolic profiles of maternal serum for 116 mothers with offspring who later developed ASD and 98 control mothers. Partial least squares discriminant analysis (PLS-DA) was employed to select metabolic features associated with air pollution exposure or autism risk in offspring. We also conducted extensive pathway enrichment analysis to elucidate potential ASD-related changes in the metabolome of pregnant women. RESULTS We extracted 4022 and 4945 metabolic features from maternal serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. After controlling for potential confounders, we identified 167 and 222 discriminative features (HILIC and C18, respectively). Pathway enrichment analysis to discriminate metabolic features associated with ASD risk indicated various metabolic pathway perturbations linked to the tricarboxylic acid (TCA) cycle and mitochondrial function, including carnitine shuttle, amino acid metabolism, bile acid metabolism, and vitamin A metabolism. CONCLUSION Using high resolution metabolomics, we identified several metabolic pathways disturbed in mothers with ASD offspring among women experiencing high exposure to traffic-related air pollution during pregnancy that were associated with mitochondrial dysfunction. These findings provide us with a better understanding of metabolic disturbances involved in the development of ASD under adverse environmental conditions.
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Affiliation(s)
- Ja Hyeong Kim
- Department of Pediatrics, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 44033, South Korea.
| | - Qi Yan
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA.
| | - Karan Uppal
- Computational Systems Medicine & Metabolomics Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, 30322, USA.
| | - Xin Cui
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Perinatal Epidemiology and Health Outcomes Research Unit, Division of Neonatology, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, 94304, USA; California Perinatal Quality Care Collaborative, Palo Alto, CA, 94305, USA.
| | - Chenxiao Ling
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA.
| | - Douglas I Walker
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Julia E Heck
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA.
| | - Ondine S von Ehrenstein
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Department of Community Health Sciences, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA.
| | - Dean P Jones
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, Emory University, Atlanta, GA, 30322, USA.
| | - Beate Ritz
- Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Department of Community Health Sciences, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA; Department of Neurology, Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
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32
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Needham BD, Adame MD, Serena G, Rose DR, Preston GM, Conrad MC, Campbell AS, Donabedian DH, Fasano A, Ashwood P, Mazmanian SK. Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder. Biol Psychiatry 2021; 89:451-462. [PMID: 33342544 PMCID: PMC7867605 DOI: 10.1016/j.biopsych.2020.09.025] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental condition with hallmark behavioral manifestations including impaired social communication and restricted repetitive behavior. In addition, many affected individuals display metabolic imbalances, immune dysregulation, gastrointestinal dysfunction, and altered gut microbiome compositions. METHODS We sought to better understand nonbehavioral features of ASD by determining molecular signatures in peripheral tissues through mass spectrometry methods (ultrahigh performance liquid chromatography-tandem mass spectrometry) with broad panels of identified metabolites. Herein, we compared the global metabolome of 231 plasma and 97 fecal samples from a large cohort of children with ASD and typically developing control children. RESULTS Differences in amino acid, lipid, and xenobiotic metabolism distinguished ASD and typically developing samples. Our results implicated oxidative stress and mitochondrial dysfunction, hormone level elevations, lipid profile changes, and altered levels of phenolic microbial metabolites. We also revealed correlations between specific metabolite profiles and clinical behavior scores. Furthermore, a summary of metabolites modestly associated with gastrointestinal dysfunction in ASD is provided, and a pilot study of metabolites that can be transferred via fecal microbial transplant into mice is identified. CONCLUSIONS These findings support a connection between metabolism, gastrointestinal physiology, and complex behavioral traits and may advance discovery and development of molecular biomarkers for ASD.
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Affiliation(s)
- Brittany D. Needham
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Mark D. Adame
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA, 02114, USA
| | - Destanie R. Rose
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA,The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | | | | | | | | | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA, 02114, USA
| | - Paul Ashwood
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA,The M.I.N.D. Institute, University of California, Davis, Sacramento, CA, 95817, USA
| | - Sarkis K. Mazmanian
- Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
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33
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Proteomics and Metabolomics Approaches towards a Functional Insight onto AUTISM Spectrum Disorders: Phenotype Stratification and Biomarker Discovery. Int J Mol Sci 2020; 21:ijms21176274. [PMID: 32872562 PMCID: PMC7504551 DOI: 10.3390/ijms21176274] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 08/25/2020] [Accepted: 08/27/2020] [Indexed: 12/19/2022] Open
Abstract
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by behavioral alterations and currently affect about 1% of children. Significant genetic factors and mechanisms underline the causation of ASD. Indeed, many affected individuals are diagnosed with chromosomal abnormalities, submicroscopic deletions or duplications, single-gene disorders or variants. However, a range of metabolic abnormalities has been highlighted in many patients, by identifying biofluid metabolome and proteome profiles potentially usable as ASD biomarkers. Indeed, next-generation sequencing and other omics platforms, including proteomics and metabolomics, have uncovered early age disease biomarkers which may lead to novel diagnostic tools and treatment targets that may vary from patient to patient depending on the specific genomic and other omics findings. The progressive identification of new proteins and metabolites acting as biomarker candidates, combined with patient genetic and clinical data and environmental factors, including microbiota, would bring us towards advanced clinical decision support systems (CDSSs) assisted by machine learning models for advanced ASD-personalized medicine. Herein, we will discuss novel computational solutions to evaluate new proteome and metabolome ASD biomarker candidates, in terms of their recurrence in the reviewed literature and laboratory medicine feasibility. Moreover, the way to exploit CDSS, performed by artificial intelligence, is presented as an effective tool to integrate omics data to electronic health/medical records (EHR/EMR), hopefully acting as added value in the near future for the clinical management of ASD.
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34
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Usui N, Iwata K, Miyachi T, Takagai S, Wakusawa K, Nara T, Tsuchiya KJ, Matsumoto K, Kurita D, Kameno Y, Wakuda T, Takebayashi K, Iwata Y, Fujioka T, Hirai T, Toyoshima M, Ohnishi T, Toyota T, Maekawa M, Yoshikawa T, Maekawa M, Nakamura K, Tsujii M, Sugiyama T, Mori N, Matsuzaki H. VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. EBioMedicine 2020; 58:102917. [PMID: 32739868 PMCID: PMC7393524 DOI: 10.1016/j.ebiom.2020.102917] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. METHODS An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. FINDINGS Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. INTERPRETATION Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. FUNDING This study was supported mainly by MEXT, Japan.
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Affiliation(s)
- Noriyoshi Usui
- Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan; Center for Medical Research and Education, and Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan; Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka 541-8567, Japan
| | - Keiko Iwata
- Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan
| | - Taishi Miyachi
- Department of Pediatrics, Nagoya City University Medical School, Aichi 467-8601, Japan
| | - Shu Takagai
- Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Keisuke Wakusawa
- Department of Rehabilitation, Miyagi Children's Hospital, Miyagi 989-3126, Japan
| | - Takahiro Nara
- Department of Rehabilitation, Miyagi Children's Hospital, Miyagi 989-3126, Japan
| | - Kenji J Tsuchiya
- Research Center for Child Mental Development, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Kaori Matsumoto
- Graduate School of Psychology, Kanazawa Institute of Technology, Ishikawa 921-8054, Japan
| | - Daisuke Kurita
- Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Yosuke Kameno
- Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Tomoyasu Wakuda
- Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Kiyokazu Takebayashi
- Department of Psychiatry, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Yasuhide Iwata
- Department of Psychiatry and Neurology, Fukude Nishi Hospital, Shizuoka 437-1216, Japan
| | - Toru Fujioka
- Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan
| | - Takaharu Hirai
- Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan; Department of Community Health Nursing, School of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Manabu Toyoshima
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
| | - Tetsuo Ohnishi
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
| | - Tomoko Toyota
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
| | - Motoko Maekawa
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
| | - Takeo Yoshikawa
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Kazuhiko Nakamura
- Department of Psychiatry, Hirosaki University School of Medicine, Aomori 036-8562, Japan
| | - Masatsugu Tsujii
- School of Contemporary Sociology, Chukyo University, Aichi 470-0393, Japan
| | - Toshiro Sugiyama
- Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan
| | - Norio Mori
- Department of Psychiatry and Neurology, Fukude Nishi Hospital, Shizuoka 437-1216, Japan
| | - Hideo Matsuzaki
- Research Center for Child Mental Development, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan; Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan; Life Science Innovation Center, University of Fukui, Fukui 910-1193, Japan.
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Ritz B, Yan Q, Uppal K, Liew Z, Cui X, Ling C, Inoue K, von Ehrenstein O, Walker DI, Jones DP. Untargeted Metabolomics Screen of Mid-pregnancy Maternal Serum and Autism in Offspring. Autism Res 2020; 13:1258-1269. [PMID: 32496662 DOI: 10.1002/aur.2311] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 03/24/2020] [Accepted: 04/15/2020] [Indexed: 12/15/2022]
Abstract
Discovering pathophysiologic networks in a blood-based approach may help to generate valuable tools for early treatment or preventive measures in autism. To date targeted or untargeted metabolomics approaches to identify metabolic features and pathways affecting fetal neurodevelopment have rarely been applied to pregnancy samples, that is, an early period potentially relevant for the development of autism spectrum disorders (ASD). We conducted a population-based study relying on autism diagnoses retrieved from California Department of Developmental Services record. After linking cases to and sampling controls from birth certificates, we retrieved stored maternal mid-pregnancy serum samples collected as part of the California Prenatal Screening Program from the California Biobank for children born 2004 to 2010 in the central valley of California. We retrieved serum for 52 mothers whose children developed autism and 62 population controls originally selected from all eligible children matched by birth year and child's sex. Also, we required that these mothers were relatively low or unexposed to air pollution and select pesticides during early pregnancy. We identified differences in metabolite levels in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N-glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21-steroid hormone biosynthesis and metabolism. Disturbances in these pathways have been shown to be relevant for neurodevelopment in rare genetic syndromes or implicated in previous studies of autism. This study provides new insight into maternal mid-pregnancy metabolic features possibly related to the development of autism and an incentive to explore whether these pathways and metabolites are useful for early diagnosis, treatment, or prevention. LAY SUMMARY: This study found that in mid-pregnancy the blood of mothers who give birth to a child that develops autism has some characteristic features that are different from those of blood samples taken from control mothers. These features are related to biologic mechanisms that can affect fetal brain development. In the future, these insights may help identify biomarkers for early autism diagnosis and treatment or preventive measures. Autism Res 2020, 13: 1258-1269. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
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Affiliation(s)
- Beate Ritz
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA.,Department of Neurology, UCLA School of Medicine, Los Angeles, California, USA
| | - Qi Yan
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Karan Uppal
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
| | - Zeyan Liew
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA.,Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Xin Cui
- Perinatal Epidemiology and Health Outcomes Research Unit, Division of Neonatology, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California, USA.,California Perinatal Quality Care Collaborative, Palo Alto, California, USA
| | - Chenxiao Ling
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Kosuke Inoue
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Ondine von Ehrenstein
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA
| | - Douglas I Walker
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dean P Jones
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA
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Park DI. Genomics, transcriptomics, proteomics and big data analysis in the discovery of new diagnostic markers and targets for therapy development. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 173:61-90. [PMID: 32711818 DOI: 10.1016/bs.pmbts.2020.04.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Highly complex endophenotypes and underlying molecular mechanisms have prevented effective diagnosis and treatment of autism spectrum disorder. Despite extensive studies to identify relevant biosignatures, no biomarker and therapeutic targets are available in the current clinical practice. While our current knowledge is still largely incomplete, -omics technology and machine learning-based big data analysis have provided novel insights on the etiology of autism spectrum disorders, elucidating systemic impairments that can be translated into biomarker and therapy target candidates. However, more integrated and sophisticated approaches are vital to realize molecular stratification and individualized treatment strategy. Ultimately, systemic approaches based on -omics and big data analysis will significantly contribute to more effective biomarker and therapy development for autism spectrum disorder.
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Affiliation(s)
- Dong Ik Park
- Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Danish National Research Foundation Center, PROMEMO, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
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Graham SF, Turkoglu O, Yilmaz A, Ustun I, Ugur Z, Bjorndhal T, Han B, Mandal R, Wishart D, Bahado-Singh RO. Targeted metabolomics highlights perturbed metabolism in the brain of autism spectrum disorder sufferers. Metabolomics 2020; 16:59. [PMID: 32333121 DOI: 10.1007/s11306-020-01685-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 04/17/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficiencies in social interactions and communication, combined with restricted and repetitive behavioral issues. OBJECTIVES As little is known about the etiopathophysiology of ASD and early diagnosis is relatively subjective, we aim to employ a targeted, fully quantitative metabolomics approach to biochemically profile post-mortem human brain with the overall goal of identifying metabolic pathways that may have been perturbed as a result of the disease while uncovering potential central diagnostic biomarkers. METHODS Using a combination of 1H NMR and DI/LC-MS/MS we quantitatively profiled the metabolome of the posterolateral cerebellum from post-mortem human brain harvested from people who suffered with ASD (n = 11) and compared them with age-matched controls (n = 10). RESULTS We accurately identified and quantified 203 metabolites in post-mortem brain extracts and performed a metabolite set enrichment analyses identifying 3 metabolic pathways as significantly perturbed (p < 0.05). These include Pyrimidine, Ubiquinone and Vitamin K metabolism. Further, using a variety of machine-based learning algorithms, we identified a panel of central biomarkers (9-hexadecenoylcarnitine (C16:1) and the phosphatidylcholine PC ae C36:1) capable of discriminating between ASD and controls with an AUC = 0.855 with a sensitivity and specificity equal to 0.80 and 0.818, respectively. CONCLUSION For the first time, we report the use of a multi-platform metabolomics approach to biochemically profile brain from people with ASD and report several metabolic pathways which are perturbed in the diseased brain of ASD sufferers. Further, we identified a panel of biomarkers capable of distinguishing ASD from control brains. We believe that these central biomarkers may be useful for diagnosing ASD in more accessible biomatrices.
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Affiliation(s)
- Stewart F Graham
- Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309, USA.
- Research Institute, Metabolomics Division, Beaumont Health, Royal Oak, MI, 48073, USA.
| | - Onur Turkoglu
- Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309, USA
| | - Ali Yilmaz
- Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309, USA
- Research Institute, Metabolomics Division, Beaumont Health, Royal Oak, MI, 48073, USA
| | - Ilyas Ustun
- Wayne State University, Civil and Environmental Engineering, Detroit, MI, USA
| | - Zafer Ugur
- Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309, USA
- Research Institute, Metabolomics Division, Beaumont Health, Royal Oak, MI, 48073, USA
| | - Trent Bjorndhal
- Department of Biological and Computing Sciences, University of Alberta, Edmonton, AB, Canada
| | - BeomSoo Han
- Department of Biological and Computing Sciences, University of Alberta, Edmonton, AB, Canada
| | - Rupa Mandal
- Department of Biological and Computing Sciences, University of Alberta, Edmonton, AB, Canada
| | - David Wishart
- Department of Biological and Computing Sciences, University of Alberta, Edmonton, AB, Canada
| | - Ray O Bahado-Singh
- Oakland University-William Beaumont School of Medicine, Rochester, MI, 48309, USA
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Abstract
In the last years, 'omics' technologies, and especially metabolomics, emerged as expanding scientific disciplines and promising technologies in the characterization of several pathophysiological processes.In detail, metabolomics, able to detect in a dynamic way the whole set of molecules of low molecular weight in cells, tissues, organs, and biological fluids, can provide a detailed phenotypic portray, representing a metabolic "snapshot."Thanks to its numerous strength points, metabolomics could become a fundamental tool in human health, allowing the exact evaluation of individual metabolic responses to pathophysiological stimuli including drugs, environmental changes, lifestyle, a great number of diseases and other epigenetics factors.Moreover, if current metabolomics data will be confirmed on larger samples, such technology could become useful in the early diagnosis of diseases, maybe even before the clinical onset, allowing a clinical monitoring of disease progression and helping in performing the best therapeutic approach, potentially predicting the therapy response and avoiding overtreatments. Moreover, the application of metabolomics in nutrition could provide significant information on the best nutrition regimen, optimal infantile growth and even in the characterization and improvement of commercial products' composition.These are only some of the fields in which metabolomics was applied, in the perspective of a precision-based, personalized care of human health.In this review, we discuss the available literature on such topic and provide some evidence regarding clinical application of metabolomics in heart diseases, auditory disturbance, nephrouropathies, adult and pediatric cancer, obstetrics, perinatal conditions like asphyxia, neonatal nutrition, neonatal sepsis and even some neuropsychiatric disorders, including autism.Our research group has been interested in metabolomics since several years, performing a wide spectrum of experimental and clinical studies, including the first metabolomics analysis of human breast milk. In the future, it is reasonable to predict that the current knowledge could be applied in daily clinical practice, and that sensible metabolomics biomarkers could be easily detected through cheap and accurate sticks, evaluating biofluids at the patient's bed, improving diagnosis, management and prognosis of sick patients and allowing a personalized medicine. A dream? May be I am a dreamer, but I am not the only one.
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Affiliation(s)
- Flaminia Bardanzellu
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU University of Cagliari, SS 554 km 4,500, 09042, Monserrato, CA, Italy.
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, AOU University of Cagliari, SS 554 km 4,500, 09042, Monserrato, CA, Italy
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Shen L, Liu X, Zhang H, Lin J, Feng C, Iqbal J. Biomarkers in autism spectrum disorders: Current progress. Clin Chim Acta 2020; 502:41-54. [DOI: 10.1016/j.cca.2019.12.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 12/10/2019] [Accepted: 12/13/2019] [Indexed: 12/13/2022]
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Higher Levels of Low Molecular Weight Sulfur Compounds and Homocysteine Thiolactone in the Urine of Autistic Children. Molecules 2020; 25:molecules25040973. [PMID: 32098164 PMCID: PMC7070266 DOI: 10.3390/molecules25040973] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/17/2020] [Accepted: 02/19/2020] [Indexed: 12/23/2022] Open
Abstract
In this study, the levels of concentration of homocysteine thiolactone (HTL), cysteine (Cys), and cysteinylglycine (CysGly) in the urine of autistic and non-autistic children were investigated and compared. HTL has never been analyzed in autistic children. The levels of low molecular weight sulfur compounds in the urine of both groups were determined by validated methods based on high-performance liquid chromatography with spectrofluorometric and diode-array detectors. The statistical data show a significant difference between the examined groups. Children with autism were characterized by a significantly higher level of HTL (p = 5.86 × 10−8), Cys (p = 1.49 × 10−10) and CysGly (p = 1.06 × 10−8) in urine compared with the control group. A difference in the p-value of <0.05 is statistically significant. Higher levels of HTL, Cys, and CysGly in the urine of 41 children with autism, aged 3 to 17, were observed. The obtained results may indicate disturbances in the metabolism of methionine, Cys, and glutathione in some autistic patients. These preliminary results suggest that further research with more rigorous designs and a large number of subjects is needed.
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Glinton KE, Elsea SH. Untargeted Metabolomics for Autism Spectrum Disorders: Current Status and Future Directions. Front Psychiatry 2019; 10:647. [PMID: 31551836 PMCID: PMC6746843 DOI: 10.3389/fpsyt.2019.00647] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 08/12/2019] [Indexed: 12/20/2022] Open
Abstract
Autism spectrum disorders (ASDs) are a group of neurodevelopment disorders characterized by childhood onset deficits in social communication and interaction. Although the exact etiology of most cases of ASDs is unknown, a portion has been proposed to be associated with various metabolic abnormalities including mitochondrial dysfunction, disorders of cholesterol metabolism, and folate abnormalities. Targeted biochemical testing like plasma amino acid and acylcarnitine profiles have demonstrated limited utility in helping to diagnose and manage such patients. Untargeted metabolomics has emerged, however, as a promising tool in screening for underlying biochemical abnormalities and managing treatment and as a means of investigating possible novel biomarkers for the disorder. Here, we review the principles and methodology behind untargeted metabolomics, recent pilot studies utilizing this technology, and areas in which it may be integrated into the care of children with this disorder in the future.
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Affiliation(s)
- Kevin E. Glinton
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Sarah H. Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
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