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Tang MB, Liu YX, Hu ZW, Luo HY, Zhang S, Shi CH, Xu YM. Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential. Front Aging Neurosci 2025; 16:1454735. [PMID: 40012862 PMCID: PMC11861300 DOI: 10.3389/fnagi.2024.1454735] [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: 06/25/2024] [Accepted: 12/30/2024] [Indexed: 02/28/2025] Open
Abstract
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.
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Affiliation(s)
- Mi-bo Tang
- Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yi-xuan Liu
- Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zheng-wei Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Hai-yang Luo
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuo Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Chang-he Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yu-ming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, Henan, China
- Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, Henan, China
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Yin H, Wang Z, Wang W, Liu J, Xue Y, Liu L, Shen J, Duan L. Dysregulated Pathways During Pregnancy Predict Drug Candidates in Neurodevelopmental Disorders. Neurosci Bull 2025:10.1007/s12264-025-01360-0. [PMID: 39913063 DOI: 10.1007/s12264-025-01360-0] [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: 04/22/2024] [Accepted: 11/06/2024] [Indexed: 02/07/2025] Open
Abstract
Maternal health during pregnancy has a direct impact on the risk and severity of neurodevelopmental disorders (NDDs) in the offspring, especially in the case of drug exposure. However, little progress has been made to assess the risk of drug exposure during pregnancy due to ethical constraints and drug use factors. We collected and manually curated sub-pathways and pathways (sub-/pathways) and drug information to propose an analytical framework for predicting drug candidates. This framework linked sub-/pathway activity and drug response scores derived from gene transcription data and was applied to human fetal brain development and six NDDs. Further, specific and pleiotropic sub-/pathways/drugs were identified using entropy, and sex bias was analyzed in conjunction with logistic regression and random forest models. We identified 19 disorder-associated and 256 regionally pleiotropic and specific candidate drugs that targeted risk sub-/pathways in NDDs, showing temporal or spatial changes across fetal development. Moreover, 5443 differential drug-sub-/pathways exhibited sex-biased differences after filling in the gender labels. A user-friendly NDDP visualization website ( https://ndd-lab.shinyapps.io/NDDP ) was developed to allow researchers and clinicians to access and retrieve data easily. Our framework overcame data gaps and identified numerous pleiotropic and specific candidates across six disorders and fetal developmental trajectories. This could significantly contribute to drug discovery during pregnancy and can be applied to a wide range of traits.
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Affiliation(s)
- Huamin Yin
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, China
| | - Zhendong Wang
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Wenhang Wang
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, China
| | - Jiaxin Liu
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, China
| | - Yirui Xue
- Wenzhou Medical University, Wenzhou, 325035, China
| | - Li Liu
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, China
| | - Jingling Shen
- Institute of Life Sciences, College of Life and Environmental Sciences, Wenzhou University, Wenzhou, 325035, China.
| | - Lian Duan
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Roy B, Vacas S, Kang DW, Aysola RS, Kumar R. Regional brain iron mapping in obstructive sleep apnea adults. Sleep Med 2025; 126:211-217. [PMID: 39700729 DOI: 10.1016/j.sleep.2024.12.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/15/2024] [Accepted: 12/15/2024] [Indexed: 12/21/2024]
Abstract
PURPOSE Obstructive sleep apnea (OSA) subjects show significant white matter injury, including myelin changes in several brain areas, potentially from impaired glial cells, contributing to increased iron levels that escalate neurodegeneration, but brain iron loads are unclear. Our aim was to examine regional brain iron load, using T2∗-relaxometry, in OSA adults before and after continuous positive airway pressure (CPAP) treatment over controls. METHODS We performed T2∗-weighted imaging using a 3.0-T MRI scanner on 35 OSA adults, who were followed after 3- and 9- mo CPAP treatment, and 67 controls. Using T2∗-weighted images, R2∗maps were calculated, normalized, and smoothed. The smoothed R2∗ maps, as well as average R2∗ values extracted from different brain regions were compared between OSA and controls using ANCOVA (covariates: age and sex) and paired t-tests in OSA adults. RESULTS Multiple brain areas in OSA showed increased R2∗ values before CPAP, indicative of higher iron, over controls and included the amygdala, insula, hippocampus, cerebellum, medulla, and pons nearby areas. The R2∗ values continued to increase in multiple sites at 3-mo CPAP treatment in OSA, and those sites included the cerebellum, thalamus, and cingulate. However, after 9-mo CPAP usage, none of the brain regions showed increased R2∗ values in OSA over baseline. CONCLUSIONS OSA patients show increased iron content in multiple sites over controls, which progressively increased in several sites, even after 3-mo CPAP use, and started to clear after 9-mo. The findings suggest a means for intervention to lessen brain injury by interfering with iron accumulation in OSA.
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Affiliation(s)
- Bhaswati Roy
- Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Susana Vacas
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, USA
| | - Daniel W Kang
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Ravi S Aysola
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Rajesh Kumar
- Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Radiology, University of California Los Angeles, Los Angeles, CA, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.
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Yang ZZ, Liu WQ, Yu HD, Yu SX, Li YR, Wang YF, Yao TF, Li WZ, Sun D, Niu L, Liu XZ, Zuo ZF. Inhibition of GZMB activity ameliorates cognitive dysfunction by reducing demyelination in diabetic mice. Free Radic Biol Med 2024; 225:53-62. [PMID: 39326683 DOI: 10.1016/j.freeradbiomed.2024.09.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 09/06/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND Diabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes. METHODS Streptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 as well as MBP and CNPase. RESULTS The GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination. CONCLUSIONS Our findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment.
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Affiliation(s)
- Zheng-Zhong Yang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Wen-Qiang Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Hong-Dan Yu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Sheng-Xue Yu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Ya-Ru Li
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Yu-Fei Wang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Tie-Feng Yao
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Wan-Ze Li
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Die Sun
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Lin Niu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Xue-Zheng Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
| | - Zhong-Fu Zuo
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
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Wright B, King S, Suphioglu C. The Importance of Phosphoinositide 3-Kinase in Neuroinflammation. Int J Mol Sci 2024; 25:11638. [PMID: 39519189 PMCID: PMC11546674 DOI: 10.3390/ijms252111638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/23/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood-brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders.
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Affiliation(s)
- Brock Wright
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia; (B.W.); (S.K.)
- Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| | - Samuel King
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia; (B.W.); (S.K.)
- Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
| | - Cenk Suphioglu
- NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia; (B.W.); (S.K.)
- Centre for Sustainable Bioproducts, School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, 75 Pigdons Road, Geelong, VIC 3216, Australia
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Shen Y, Liu F, Zhang M. Therapeutic potential of plant-derived natural compounds in Alzheimer's disease: Targeting microglia-mediated neuroinflammation. Biomed Pharmacother 2024; 178:117235. [PMID: 39094545 DOI: 10.1016/j.biopha.2024.117235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/27/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024] Open
Abstract
Microglia are resident immune cells of the central nervous system (CNS) with roles in sensing, housekeeping, and defense. Exploring the role of microglia in the occurrence and development of Alzheimer's disease (AD) and the possible therapeutic mechanism of plant-derived natural compounds (PDNCs) that regulate microglia-associated neuroinflammation may potentially help in elucidating the pathogenesis of AD and provide novel insights for its treatment. This review explores the role of abnormal microglial activation and its dominant neuroinflammatory response, as well as the activation of their target receptors and signaling pathways in AD pathogenesis. Additionally, we report an update on the potential pharmacological mechanisms of multiple PDNCs in modulating microglia-associated neuroinflammation in AD treatment. Dysregulated activation of microglial receptors and their downstream pathways impaired immune homeostasis in animal models of AD. Multiple signaling pathways, such as mitogen-activated protein kinase (MAPK), nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and Toll-like receptors, play important roles in microglial activation and can exacerbate microglia-mediated neuroinflammation. PDNCs, such as magnolol, stigmasterol, matrine, naringenin, naringin, and resveratrol, can delay the progression of AD by inhibiting the proinflammatory receptors of microglia, activating its anti-inflammatory receptors, regulating the receptors related to β-amyloid (Aβ) clearance, reversing immune dysregulation, and maintaining the immune homeostasis of microglial downstream pathways. This review summarizes the mechanisms by which microglia cause chronic inflammation in AD and evaluates the beneficial effects of PDNCs on immune regulation in AD by regulating microglial receptors and their downstream pathways.
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Affiliation(s)
- Yanyan Shen
- Department of Neurosurgery, Shengjing Hospital of China Medical University, China.
| | - Fang Liu
- Department of Neurology, The First Affiliated Hospital of China Medical University, China
| | - Mingjie Zhang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, China.
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Liu H, Yi J, Zhang C, Li Y, Wang Q, Wang S, Dai S, Zheng Z, Jiang T, Gao P, Xue A, Huang Z, Kong F, Wang Y, He B, Guo X, Li Q, Chen J, Yin G, Zhao S. Macrophage GIT1 promotes oligodendrocyte precursor cell differentiation and remyelination after spinal cord injury. Glia 2024; 72:1674-1692. [PMID: 38899731 DOI: 10.1002/glia.24577] [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: 08/29/2023] [Revised: 05/02/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024]
Abstract
Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.
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Affiliation(s)
- Hao Liu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiang Yi
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Orthopedics, Yancheng Third People's Hospital, Yancheng, Jiangsu, China
| | - Chenxi Zhang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yin Li
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qian Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shenyu Wang
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Siming Dai
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ziyang Zheng
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tao Jiang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peng Gao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ao Xue
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhenfei Huang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fanqi Kong
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yongxiang Wang
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou, China
- Northern Jiangsu People's Hospital, Yangzhou, China
| | - Baorong He
- Department of Spine Surgery, Honghui-hospital, Xi'an Jiaotong Uinversity, School of Medicine, Xi'an, China
| | - Xiaodong Guo
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingqing Li
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jian Chen
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoyong Yin
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shujie Zhao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Ahmed Mohamed Z, Yang J, Wen J, Jia F, Banerjee S. SEPHS1 Gene: A new master key for neurodevelopmental disorders. Clin Chim Acta 2024; 562:119844. [PMID: 38960024 DOI: 10.1016/j.cca.2024.119844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 06/30/2024] [Accepted: 06/30/2024] [Indexed: 07/05/2024]
Abstract
The SEPHS1 (Selenophosphate Synthetase 1) gene encodes a critical enzyme for synthesizing selenophosphate, the active donor of selenium (Se) necessary for selenoprotein biosynthesis. Selenoproteins are vital for antioxidant defense, thyroid hormone metabolism, and cellular homeostasis. Mutations in SEPHS1 gene, are associated with neurodevelopmental disorders with developmental delay, poor growth, hypotonia, and dysmorphic features. Due to Se's critical role in brain development and function, SEPHS1 gene has taken center stage in neurodevelopmental research. This review explores the structure and function of the SEPHS1 gene, its role in neurodevelopment, and the implications of its dysregulation for neurodevelopmental disorders. Therapeutic strategies, including Se supplementation, gene therapy, and targeted therapies, are discussed as potential interventions to address SEPHS1 associated neurodevelopmental dysfunction. The study's findings reveal how SEPHS1 mutations disrupt neurodevelopment, emphasizing the gene's intolerance to loss of function. Future research should focus on functional characterization of SEPHS1 variants, broader genetic screenings, and therapeutic developments.
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Affiliation(s)
- Zakaria Ahmed Mohamed
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Jianli Yang
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Jianping Wen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Feiyong Jia
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Santasree Banerjee
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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9
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Leenders F, Koole L, Slaets H, Tiane A, Hove DVD, Vanmierlo T. Navigating oligodendrocyte precursor cell aging in brain health. Mech Ageing Dev 2024; 220:111959. [PMID: 38950628 DOI: 10.1016/j.mad.2024.111959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/17/2024] [Accepted: 06/24/2024] [Indexed: 07/03/2024]
Abstract
Oligodendrocyte precursor cells (OPCs) comprise 5-8 % of the adult glial cell population and stand out as the most proliferative cell type in the central nervous system (CNS). OPCs are responsible for generating oligodendrocytes (OLs), the myelinating cells of the CNS. However, OPC functions decline as we age, resulting in impaired differentiation and inadequate remyelination. This review explores the cellular and molecular changes associated with OPC aging, and their impact on OPC differentiation and functionality. Furthermore, it examines the impact of OPC aging within the context of multiple sclerosis and Alzheimer's disease, both neurodegenerative conditions wherein aged OPCs exacerbate disease progression by impeding remyelination. Moreover, various pharmacological interventions targeting pathways related to senescence and differentiation are discussed as potential strategies to rejuvenate aged OPCs. Enhancing our understanding of OPC aging mechanisms holds promise for developing new therapies to improve remyelination and repair in age-related neurodegenerative disorders.
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Affiliation(s)
- Freddy Leenders
- Department Psychiatry and Neuropsychology, Division Translational Neuroscience, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
| | - Lisa Koole
- Department Psychiatry and Neuropsychology, Division Translational Neuroscience, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
| | - Helena Slaets
- University MS Centre (UMSC) Hasselt, Pelt, Belgium; Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Assia Tiane
- Department Psychiatry and Neuropsychology, Division Translational Neuroscience, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; University MS Centre (UMSC) Hasselt, Pelt, Belgium
| | - Daniel van den Hove
- Department Psychiatry and Neuropsychology, Division Translational Neuroscience, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands
| | - Tim Vanmierlo
- Department Psychiatry and Neuropsychology, Division Translational Neuroscience, Mental Health and Neuroscience Research Institute, Maastricht University, Maastricht, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; University MS Centre (UMSC) Hasselt, Pelt, Belgium.
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10
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Khelfaoui H, Ibaceta-Gonzalez C, Angulo MC. Functional myelin in cognition and neurodevelopmental disorders. Cell Mol Life Sci 2024; 81:181. [PMID: 38615095 PMCID: PMC11016012 DOI: 10.1007/s00018-024-05222-2] [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: 12/08/2023] [Revised: 03/18/2024] [Accepted: 03/30/2024] [Indexed: 04/15/2024]
Abstract
In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays a crucial role in the transmission of neuronal information by promoting the rapid saltatory conduction of action potentials and providing neurons with structural and metabolic support. Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally recognized as a universal evolutionary innovation to respond quickly to the environment: myelin helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring precision. Its principal function could be to coordinate various neuronal networks, promoting their synchronization through oscillations (or rhythms) relevant for specific information processing tasks. Interestingly, myelin has been directly involved in different types of cognitive processes relying on brain oscillations, and myelin plasticity is currently considered to be part of the fundamental mechanisms for memory formation and maintenance. However, despite ample evidence showing the involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully understood. In this review, we aim to highlight what is known and what remains to be explored to understand the role of myelin in high order brain processes.
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Affiliation(s)
- Hasni Khelfaoui
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, 75014, Paris, France
| | - Cristobal Ibaceta-Gonzalez
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, 75014, Paris, France
| | - Maria Cecilia Angulo
- Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, 75014, Paris, France.
- GHU-PARIS Psychiatrie Et Neurosciences, Hôpital Sainte Anne, 75014, Paris, France.
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11
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Primak A, Bozov K, Rubina K, Dzhauari S, Neyfeld E, Illarionova M, Semina E, Sheleg D, Tkachuk V, Karagyaur M. Morphogenetic theory of mental and cognitive disorders: the role of neurotrophic and guidance molecules. Front Mol Neurosci 2024; 17:1361764. [PMID: 38646100 PMCID: PMC11027769 DOI: 10.3389/fnmol.2024.1361764] [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: 12/26/2023] [Accepted: 03/04/2024] [Indexed: 04/23/2024] Open
Abstract
Mental illness and cognitive disorders represent a serious problem for the modern society. Many studies indicate that mental disorders are polygenic and that impaired brain development may lay the ground for their manifestation. Neural tissue development is a complex and multistage process that involves a large number of distant and contact molecules. In this review, we have considered the key steps of brain morphogenesis, and the major molecule families involved in these process. The review provides many indications of the important contribution of the brain development process and correct functioning of certain genes to human mental health. To our knowledge, this comprehensive review is one of the first in this field. We suppose that this review may be useful to novice researchers and clinicians wishing to navigate the field.
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Affiliation(s)
- Alexandra Primak
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Kirill Bozov
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Kseniya Rubina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Stalik Dzhauari
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Elena Neyfeld
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
- Federal State Budgetary Educational Institution of the Higher Education “A.I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Maria Illarionova
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Ekaterina Semina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Dmitriy Sheleg
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
- Federal State Budgetary Educational Institution of the Higher Education “A.I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Vsevolod Tkachuk
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia
| | - Maxim Karagyaur
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Moscow, Russia
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12
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Jearjaroen P, Thangwong P, Tocharus C, Chaichompoo W, Suksamrarn A, Tocharus J. Hexahydrocurcumin attenuated demyelination and improved cognitive impairment in chronic cerebral hypoperfusion rats. Inflammopharmacology 2024; 32:1531-1544. [PMID: 38153537 DOI: 10.1007/s10787-023-01406-7] [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: 08/01/2023] [Accepted: 11/27/2023] [Indexed: 12/29/2023]
Abstract
Age-related white matter lesions (WML) frequently present vascular problems by decreasing cerebral blood supply, resulting in the condition known as chronic cerebral hypoperfusion (CCH). This study aimed to investigate the effect of hexahydrocurcumin (HHC) on the processes of demyelination and remyelination induced by the model of the Bilateral Common Carotid Artery Occlusion (BCCAO) for 29 days to mimic the CCH condition. The pathological appearance of myelin integrity was significantly altered by CCH, as evidenced by Transmission Electron Microscopy (TEM) and Luxol Fast Blue (LFB) staining. In addition, CCH activated A1-astrocytes and reactive-microglia by increasing the expression of Glial fibrillary acidic protein (GFAP), complement 3 (C3d) and pro-inflammatory cytokines. However, S100a10 expression, a marker of neuroprotective astrocytes, was suppressed, as were regenerative factors including (IGF-1) and Transglutaminase 2 (TGM2). Therefore, the maturation step was obstructed as shown by decreases in the levels of myelin basic protein (MBP) and the proteins related with lipid synthesis. Cognitive function was therefore impaired in the CCH model, as evidenced by the Morris water maze test. By contrast, HHC treatment significantly improved myelin integrity, and inhibited A1-astrocytes and reactive-microglial activity. Consequently, pro-inflammatory cytokines and A1-astrocytes were attenuated, and regenerative factors increased assisting myelin maturation and hence improving cognitive performance. In conclusion, HHC improves cognitive function and also the integrity of white matter in CCH rats by reducing demyelination, and pro-inflammatory cytokine production and promoting the process of remyelination.
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Affiliation(s)
- Pranglada Jearjaroen
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Phakkawat Thangwong
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chianqg Mai, Thailand
| | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Functional Food Research Center for Well-Being, Multidisciplinary Research Institute, Chiang Mai University, Chiang Mai, Thailand.
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13
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Huang H, Zhang KP, Sun KK, Yu G. Association between type 2 inflammatory diseases and neurodevelopmental disorders in low-birth-weight children and adolescents. Front Psychol 2024; 15:1292071. [PMID: 38455122 PMCID: PMC10918750 DOI: 10.3389/fpsyg.2024.1292071] [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: 09/10/2023] [Accepted: 01/31/2024] [Indexed: 03/09/2024] Open
Abstract
Background Evidence of the association of certain neurodevelopmental disorder with specific type 2 inflammatory (T2) disease has been found. However, the association of various neurodevelopmental disorders with T2 diseases as a whole remains unclear in low-birth-weight (LBW) infants. Objective To evaluate the association of type 2 inflammatory (T2) diseases with intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and learning disability (LD) in LBW children and adolescents. Methods The study sample was derived from 2005 to 2018 National Health Interview Survey sample child files. LBW children and adolescents aged 3-17 were included. History of T2 diseases (including asthma and atopic dermatitis) and four neurodevelopmental disorders were reported by adults in families. The relationship between T2 diseases and the risk of four neurodevelopmental disorders was investigated through multiple-weighted logistic regression. Age, sex, race/ethnicity, region, highest education in family and ratio of family income to the poverty threshold were adjusted as covariates for model estimation. Subgroup analyses were conducted by age stratification (3-11 and 12-17 years), sex (male and female), and race (white and non-white). Results 11,260 LBW children aged 3-17 years [mean age (SE), 9.73 (0.05) years] were included, in which 3,191 children had T2 diseases. History of T2 diseases was associated with an increased risk of neurodevelopmental disorders, with an OR of 1.35 (95% CI, 0.99-1.84) for ID, 1.47 (95% CI, 1.05-2.05) for ASD, 1.81 (95% CI, 1.51-2.16) for ADHD, and 1.74 (95% CI, 1.49-2.04) for LD following the adjustment of all the covariates. The correlations between T2 disorders and each of the four neurodevelopmental disorders were significantly different by sex and race (all P for interaction < 0.001), and no differences were found in age stratification (all P for interaction > 0.05). Conclusion In a nationally representative sample of children, we found a significant association of T2 diseases with ASD, ADHD, and LD, even after adjusting for demographic baseline. We also found that the association of T2 disease with neurodevelopmental disorders differed between sex and race. Further investigation is needed to evaluate causal relationships and elucidate their potential mechanisms.
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Affiliation(s)
- Hengye Huang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kelvin Pengyuan Zhang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States
| | - Karol Kexin Sun
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - Guangjun Yu
- Shanghai Engineering Research Center for Big Data in Pediatric Precision Medicine, Center for Biomedical Informatics, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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14
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Feng L, Chao J, Zhang M, Pacquing E, Hu W, Shi Y. Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases. iScience 2023; 26:108037. [PMID: 37867939 PMCID: PMC10589867 DOI: 10.1016/j.isci.2023.108037] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 08/11/2023] [Accepted: 09/21/2023] [Indexed: 10/24/2023] Open
Abstract
Myelin defects cause a collection of myelin disorders in the brain. The lack of human models has limited us from better understanding pathological mechanisms of myelin diseases. While human induced pluripotent stem cell (hiPSC)-derived spheroids or organoids have been used to study brain development and disorders, it has been difficult to recapitulate mature myelination in these structures. Here, we have developed a method to generate three-dimensional (3D) myelin spheroids from hiPSCs in a robust and reproducible manner. Using this method, we generated myelin spheroids from patient iPSCs to model Canavan disease (CD), a demyelinating disorder. By using CD patient iPSC-derived myelin spheroids treated with N-acetyl-aspartate (NAA), we were able to recapitulate key pathological features of the disease and show that high-level NAA is sufficient to induce toxicity on myelin sheaths. Our study has established a 3D human cellular platform to model human myelin diseases for mechanistic studies and drug discovery.
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Affiliation(s)
- Lizhao Feng
- Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
- Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou, Zhejiang 325000, China
| | - Jianfei Chao
- Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Mingzi Zhang
- Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Elizabeth Pacquing
- Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Weidong Hu
- Department of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Yanhong Shi
- Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
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15
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Fotiadis P, Cieslak M, He X, Caciagli L, Ouellet M, Satterthwaite TD, Shinohara RT, Bassett DS. Myelination and excitation-inhibition balance synergistically shape structure-function coupling across the human cortex. Nat Commun 2023; 14:6115. [PMID: 37777569 PMCID: PMC10542365 DOI: 10.1038/s41467-023-41686-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 09/08/2023] [Indexed: 10/02/2023] Open
Abstract
Recent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders.
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Affiliation(s)
- Panagiotis Fotiadis
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
| | - Matthew Cieslak
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Xiaosong He
- Department of Psychology, University of Science and Technology of China, Hefei, Anhui, 230026, China
| | - Lorenzo Caciagli
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Mathieu Ouellet
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Theodore D Satterthwaite
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Russell T Shinohara
- Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Center for Biomedical Image Computing & Analytics, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Dani S Bassett
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Electrical & Systems Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Santa Fe Institute, Santa Fe, NM, 87501, USA.
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16
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Mrdjen D, Amouzgar M, Cannon B, Liu C, Spence A, McCaffrey E, Bharadwaj A, Tebaykin D, Bukhari S, Hartmann FJ, Kagel A, Vijayaragavan K, Oliveria JP, Yakabi K, Serrano GE, Corrada MM, Kawas CH, Camacho C, Bosse M, Tibshirani R, Beach TG, Angelo M, Montine T, Bendall SC. Spatial proteomics reveals human microglial states shaped by anatomy and neuropathology. RESEARCH SQUARE 2023:rs.3.rs-2987263. [PMID: 37398389 PMCID: PMC10312937 DOI: 10.21203/rs.3.rs-2987263/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Microglia are implicated in aging, neurodegeneration, and Alzheimer's disease (AD). Traditional, low-plex, imaging methods fall short of capturing in situ cellular states and interactions in the human brain. We utilized Multiplexed Ion Beam Imaging (MIBI) and data-driven analysis to spatially map proteomic cellular states and niches in healthy human brain, identifying a spectrum of microglial profiles, called the microglial state continuum (MSC). The MSC ranged from senescent-like to active proteomic states that were skewed across large brain regions and compartmentalized locally according to their immediate microenvironment. While more active microglial states were proximal to amyloid plaques, globally, microglia significantly shifted towards a, presumably, dysfunctional low MSC in the AD hippocampus, as confirmed in an independent cohort (n=26). This provides an in situ single cell framework for mapping human microglial states along a continuous, shifting existence that is differentially enriched between healthy brain regions and disease, reinforcing differential microglial functions overall.
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Affiliation(s)
- Dunja Mrdjen
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Meelad Amouzgar
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Bryan Cannon
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Candace Liu
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Angie Spence
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Erin McCaffrey
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Anusha Bharadwaj
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Dmitry Tebaykin
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Syed Bukhari
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Felix J. Hartmann
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
- Systems Immunology and Single-Cell Biology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Adam Kagel
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Kausalia Vijayaragavan
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - John Paul Oliveria
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Koya Yakabi
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | | | - Maria M. Corrada
- Department of Neurology, University of California, Irvine, 9269, CA, USA
| | - Claudia H. Kawas
- Department of Neurology, University of California, Irvine, 9269, CA, USA
| | - Christine Camacho
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Marc Bosse
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Robert Tibshirani
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Thomas G. Beach
- Banner Sun Health Research Institute, Sun City, 85351, AZ, USA
| | - Michael Angelo
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Thomas Montine
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
| | - Sean C. Bendall
- Department of Pathology, Stanford University, School of Medicine, Palo Alto 94304, CA, USA
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17
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Abdelwahab T, Stadler D, Knöpper K, Arampatzi P, Saliba AE, Kastenmüller W, Martini R, Groh J. Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in PLP1 mutant mice. iScience 2023; 26:106698. [PMID: 37182098 PMCID: PMC10172788 DOI: 10.1016/j.isci.2023.106698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/06/2023] [Accepted: 04/13/2023] [Indexed: 05/16/2023] Open
Abstract
Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct PLP1 mutations result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates T cell recruitment and neural damage, while later targeting of CNS-associated T cell populations is inefficient. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
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Affiliation(s)
- Tassnim Abdelwahab
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany
| | - David Stadler
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany
| | - Konrad Knöpper
- Institute for Systems Immunology, University of Würzburg, Würzburg, Germany
| | | | - Antoine-Emmanuel Saliba
- Helmholtz Institute for RNA-based Infection Research, Helmholtz-Center for Infection Research, Würzburg, Germany
| | | | - Rudolf Martini
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany
| | - Janos Groh
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany
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18
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Li Z, Jiang Z, Lu L, Liu Y. Microfluidic Manipulation for Biomedical Applications in the Central and Peripheral Nervous Systems. Pharmaceutics 2023; 15:pharmaceutics15010210. [PMID: 36678839 PMCID: PMC9862045 DOI: 10.3390/pharmaceutics15010210] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/04/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Physical injuries and neurodegenerative diseases often lead to irreversible damage to the organizational structure of the central nervous system (CNS) and peripheral nervous system (PNS), culminating in physiological malfunctions. Investigating these complex and diverse biological processes at the macro and micro levels will help to identify the cellular and molecular mechanisms associated with nerve degeneration and regeneration, thereby providing new options for the development of new therapeutic strategies for the functional recovery of the nervous system. Due to their distinct advantages, modern microfluidic platforms have significant potential for high-throughput cell and organoid cultures in vitro, the synthesis of a variety of tissue engineering scaffolds and drug carriers, and observing the delivery of drugs at the desired speed to the desired location in real time. In this review, we first introduce the types of nerve damage and the repair mechanisms of the CNS and PNS; then, we summarize the development of microfluidic platforms and their application in drug carriers. We also describe a variety of damage models, tissue engineering scaffolds, and drug carriers for nerve injury repair based on the application of microfluidic platforms. Finally, we discuss remaining challenges and future perspectives with regard to the promotion of nerve injury repair based on engineered microfluidic platform technology.
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19
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Russo M, Graham B, Santarelli DM. Gabapentin-Friend or foe? Pain Pract 2023; 23:63-69. [PMID: 36300903 PMCID: PMC10092611 DOI: 10.1111/papr.13165] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/19/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND Gabapentin is a recommended first-line agent for treating neuropathic pain; however, its efficacy rate is reportedly low, and the risk of adverse events is high. A plausible explanation for this lies with its wide range of actions, the entirety of which have yet to be fully elucidated. METHODS A review of the literature was conducted on gabapentin's known and proposed analgesic mechanisms of action, as well as potentially opposing or detrimental actions. RESULTS Gabapentin's classical analgesic mechanisms involve direct attenuation of excitatory neurotransmission in the spinal cord via inhibition of neuronal ion channels, while indirect mechanisms include descending inhibition and block of injury-evoked synaptogenesis. Glial effects have also been reported; however, whether they are neuroprotective or detrimental is unknown. Furthermore, data from animal models do not reflect clinical outcomes. CONCLUSIONS Gabapentin's clinical use should be reconsidered according to the net effects of its numerous assumed actions, including the tripartite synapse and oligodendrocyte effects. Whether it is doing more harm than good, especially in the scenarios of incomplete or loss of response, warrants consideration when prescribing gabapentin.
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Affiliation(s)
- Marc Russo
- Hunter Pain Specialists, Broadmeadow, New South Wales, Australia.,Genesis Research Services, Broadmeadow, New South Wales, Australia.,School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia
| | - Brett Graham
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia
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20
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Lysko DE, Talbot WS. Unmyelinated sensory neurons use Neuregulin signals to promote myelination of interneurons in the CNS. Cell Rep 2022; 41:111669. [PMID: 36384112 PMCID: PMC9719401 DOI: 10.1016/j.celrep.2022.111669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 09/06/2022] [Accepted: 10/25/2022] [Indexed: 11/17/2022] Open
Abstract
The signaling mechanisms neurons use to modulate myelination of circuits in the central nervous system (CNS) are only partly understood. Through analysis of isoform-specific neuregulin1 (nrg1) mutants in zebrafish, we demonstrate that nrg1 type II is an important regulator of myelination of two classes of spinal cord interneurons. Surprisingly, nrg1 type II expression is prominent in unmyelinated Rohon-Beard sensory neurons, whereas myelination of neighboring interneurons is reduced in nrg1 type II mutants. Cell-type-specific loss-of-function studies indicate that nrg1 type II is required in Rohon-Beard neurons to signal to other neurons, not oligodendrocytes, to modulate spinal cord myelination. Together, our data support a model in which unmyelinated neurons express Nrg1 type II proteins to regulate myelination of neighboring neurons, a mode of action that may coordinate the functions of unmyelinated and myelinated neurons in the CNS.
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Affiliation(s)
- Daniel E Lysko
- Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA
| | - William S Talbot
- Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
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21
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Granata L, Gildawie KR, Ismail N, Brenhouse HC, Kopec AM. Immune signaling as a node of interaction between systems that sex-specifically develop during puberty and adolescence. Dev Cogn Neurosci 2022; 57:101143. [PMID: 35933922 PMCID: PMC9357835 DOI: 10.1016/j.dcn.2022.101143] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/08/2022] [Accepted: 08/01/2022] [Indexed: 01/18/2023] Open
Abstract
Adolescence is pivotal for neural and behavioral development across species. During this period, maturation occurs in several biological systems, the most well-recognized being activation of the hypothalamic-pituitary-gonadal axis marking pubertal onset. Increasing comparative studies of sex differences have enriched our understanding of systems integration during neurodevelopment. In recent years, immune signaling has emerged as a key node of interaction between a variety of biological signaling processes. Herein, we review the age- and sex-specific changes that occur in neural, hypothalamic-pituitary, and microbiome systems during adolescence. We then describe how immune signaling interacts with these systems, and review recent preclinical evidence indicating that immune signaling may play a central role in integrating changes in their typical and atypical development during adolescence. Finally, we discuss the translational relevance of these preclinical studies to human health and wellness.
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Affiliation(s)
- Lauren Granata
- Northeastern University, 125 Nightingale Hall, Boston, MA 02115, USA.
| | - Kelsea R Gildawie
- Tufts University Cummings School of Veterinary Medicine, 200 Westboro Rd. North Grafton, MA 01536, USA.
| | - Nafissa Ismail
- University of Ottawa, 136 Jean-Jacques Lussier, Vanier Hall 2076A, Ottawa, ON K1N 6N5 Canada.
| | | | - Ashley M Kopec
- Albany Medical College, 43 New Scotland Ave., Albany, NY 12208, USA.
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22
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Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front Cell Neurosci 2022; 16:888232. [PMID: 35614970 PMCID: PMC9124899 DOI: 10.3389/fncel.2022.888232] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/13/2022] [Indexed: 12/20/2022] Open
Abstract
Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features - post exertional malaise and decreased cerebral blood flow - are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
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Affiliation(s)
- Herbert Renz-Polster
- Division of General Medicine, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medicine Mannheim, Heidelberg University, Mannheim, Germany
| | - Marie-Eve Tremblay
- Axe Neurosciences, Centre de recherche du CHU de Québec, Université Laval, Quebec, QC, Canada
- Département de Médecine Moléculaire, Université Laval, Quebec, QC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Center for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Dorothee Bienzle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Joachim E. Fischer
- Division of General Medicine, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medicine Mannheim, Heidelberg University, Mannheim, Germany
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23
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Scalabrino G. Newly Identified Deficiencies in the Multiple Sclerosis Central Nervous System and Their Impact on the Remyelination Failure. Biomedicines 2022; 10:biomedicines10040815. [PMID: 35453565 PMCID: PMC9026986 DOI: 10.3390/biomedicines10040815] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 12/14/2022] Open
Abstract
The pathogenesis of multiple sclerosis (MS) remains enigmatic and controversial. Myelin sheaths in the central nervous system (CNS) insulate axons and allow saltatory nerve conduction. MS brings about the destruction of myelin sheaths and the myelin-producing oligodendrocytes (ODCs). The conundrum of remyelination failure is, therefore, crucial in MS. In this review, the roles of epidermal growth factor (EGF), normal prions, and cobalamin in CNS myelinogenesis are briefly summarized. Thereafter, some findings of other authors and ourselves on MS and MS-like models are recapitulated, because they have shown that: (a) EGF is significantly decreased in the CNS of living or deceased MS patients; (b) its repeated administration to mice in various MS-models prevents demyelination and inflammatory reaction; (c) as was the case for EGF, normal prion levels are decreased in the MS CNS, with a strong correspondence between liquid and tissue levels; and (d) MS cobalamin levels are increased in the cerebrospinal fluid, but decreased in the spinal cord. In fact, no remyelination can occur in MS if these molecules (essential for any form of CNS myelination) are lacking. Lastly, other non-immunological MS abnormalities are reviewed. Together, these results have led to a critical reassessment of MS pathogenesis, partly because EGF has little or no role in immunology.
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Affiliation(s)
- Giuseppe Scalabrino
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy
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24
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Valdés-Tovar M, Rodríguez-Ramírez AM, Rodríguez-Cárdenas L, Sotelo-Ramírez CE, Camarena B, Sanabrais-Jiménez MA, Solís-Chagoyán H, Argueta J, López-Riquelme GO. Insights into myelin dysfunction in schizophrenia and bipolar disorder. World J Psychiatry 2022; 12:264-285. [PMID: 35317338 PMCID: PMC8900585 DOI: 10.5498/wjp.v12.i2.264] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/10/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.
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Affiliation(s)
- Marcela Valdés-Tovar
- Departamento de Farmacogenética, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | | | - Leslye Rodríguez-Cárdenas
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Carlo E Sotelo-Ramírez
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
- Doctorado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
| | - Beatriz Camarena
- Departamento de Farmacogenética, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | | | - Héctor Solís-Chagoyán
- Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Jesús Argueta
- Doctorado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico
- Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City 14370, Mexico
| | - Germán Octavio López-Riquelme
- Laboratorio de Socioneurobiología, Centro de Investigación en Ciencias Cognitivas, Universidad del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico
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25
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Leyrolle Q, Decoeur F, Dejean C, Brière G, Leon S, Bakoyiannis I, Baroux E, Sterley TL, Bosch-Bouju C, Morel L, Amadieu C, Lecours C, St-Pierre MK, Bordeleau M, De Smedt-Peyrusse V, Séré A, Schwendimann L, Grégoire S, Bretillon L, Acar N, Joffre C, Ferreira G, Uricaru R, Thebault P, Gressens P, Tremblay ME, Layé S, Nadjar A. N-3 PUFA deficiency disrupts oligodendrocyte maturation and myelin integrity during brain development. Glia 2022; 70:50-70. [PMID: 34519378 DOI: 10.1002/glia.24088] [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: 03/24/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/14/2022]
Abstract
Westernization of dietary habits has led to a progressive reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental disorders, conditions in which myelination processes are abnormal, leading to defects in brain functional connectivity. Only little is known about the role of n-3 PUFAs in oligodendrocyte physiology and white matter development. Here, we show that lifelong n-3 PUFA deficiency disrupts oligodendrocytes maturation and myelination processes during the postnatal period in mice. This has long-term deleterious consequences on white matter organization and hippocampus-prefrontal functional connectivity in adults, associated with cognitive and emotional disorders. Promoting developmental myelination with clemastine, a first-generation histamine antagonist and enhancer of oligodendrocyte precursor cell differentiation, rescues memory deficits in n-3 PUFA deficient animals. Our findings identify a novel mechanism through which n-3 PUFA deficiency alters brain functions by disrupting oligodendrocyte maturation and brain myelination during the neurodevelopmental period.
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Affiliation(s)
- Quentin Leyrolle
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France.,Université de Paris, NeuroDiderot, Inserm, Paris, France
| | - Fanny Decoeur
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Cyril Dejean
- Université de Bordeaux, INSERM, Magendie, U1215, F-3300, Bordeaux, France
| | | | - Stephane Leon
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | | | - Emilie Baroux
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Tony-Lee Sterley
- Hotchkiss Brain Institute and the Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | | | - Lydie Morel
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Camille Amadieu
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Cynthia Lecours
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada.,Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Marie-Kim St-Pierre
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada.,Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada
| | - Maude Bordeleau
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada.,Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.,Integrated Program in Neuroscience, McGill University, Montréal, Québec City, Québec, Canada
| | | | - Alexandran Séré
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | | | - Stephane Grégoire
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Lionel Bretillon
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Niyazi Acar
- Eye and Nutrition Research Group, Centre des Sciences du Goût et de l'Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, Dijon, France
| | - Corinne Joffre
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Guillaume Ferreira
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Raluca Uricaru
- CNRS, Bordeaux INP, LaBRI, UMR 5800, F-33400, Talence, France
| | | | | | - Marie-Eve Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada.,Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.,Neurology and Neurosurgery Department, McGill University, Montreal, Québec City, Québec, Canada.,Department of Molecular Medicine, Université Laval, Québec City, Québec, Canada.,Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Sophie Layé
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France
| | - Agnes Nadjar
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France.,Université de Bordeaux, INSERM, Magendie, U1215, F-3300, Bordeaux, France.,Institut Universitaire de France, Paris, France
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26
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Lanciotti A, Brignone MS, Macioce P, Visentin S, Ambrosini E. Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies. Int J Mol Sci 2021; 23:ijms23010274. [PMID: 35008700 PMCID: PMC8745131 DOI: 10.3390/ijms23010274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 12/11/2022] Open
Abstract
Astrocytes are very versatile cells, endowed with multitasking capacities to ensure brain homeostasis maintenance from brain development to adult life. It has become increasingly evident that astrocytes play a central role in many central nervous system pathologies, not only as regulators of defensive responses against brain insults but also as primary culprits of the disease onset and progression. This is particularly evident in some rare leukodystrophies (LDs) where white matter/myelin deterioration is due to primary astrocyte dysfunctions. Understanding the molecular defects causing these LDs may help clarify astrocyte contribution to myelin formation/maintenance and favor the identification of possible therapeutic targets for LDs and other CNS demyelinating diseases. To date, the pathogenic mechanisms of these LDs are poorly known due to the rarity of the pathological tissue and the failure of the animal models to fully recapitulate the human diseases. Thus, the development of human induced pluripotent stem cells (hiPSC) from patient fibroblasts and their differentiation into astrocytes is a promising approach to overcome these issues. In this review, we discuss the primary role of astrocytes in LD pathogenesis, the experimental models currently available and the advantages, future evolutions, perspectives, and limitations of hiPSC to study pathologies implying astrocyte dysfunctions.
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Affiliation(s)
- Angela Lanciotti
- Department of Neuroscience, Istituto Superiore di Sanità, 00169 Rome, Italy; (A.L.); (M.S.B.); (P.M.)
| | - Maria Stefania Brignone
- Department of Neuroscience, Istituto Superiore di Sanità, 00169 Rome, Italy; (A.L.); (M.S.B.); (P.M.)
| | - Pompeo Macioce
- Department of Neuroscience, Istituto Superiore di Sanità, 00169 Rome, Italy; (A.L.); (M.S.B.); (P.M.)
| | - Sergio Visentin
- National Center for Research and Preclinical and Clinical Evaluation of Drugs, Istituto Superiore di Sanità, 00169 Rome, Italy;
| | - Elena Ambrosini
- Department of Neuroscience, Istituto Superiore di Sanità, 00169 Rome, Italy; (A.L.); (M.S.B.); (P.M.)
- Correspondence: ; Tel.: +39-064-990-2037
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27
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Lin J, Zhou L, Luo Z, Adam MI, Zhao L, Wang F, Luo D. Flow cytometry analysis of immune and glial cells in a trigeminal neuralgia rat model. Sci Rep 2021; 11:23569. [PMID: 34876649 PMCID: PMC8651642 DOI: 10.1038/s41598-021-02911-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 11/09/2021] [Indexed: 12/02/2022] Open
Abstract
Microvascular compression of the trigeminal root entry zone (TREZ) is the main cause of most primary trigeminal neuralgia (TN), change of glial plasticity was previously studied in the TREZ of TN rat model induced by chronic compression. To better understand the role of astrocytes and immune cells in the TREZ, different cell markers including glial fibrillary acidic protein (GFAP), complement C3, S100A10, CD45, CD11b, glutamate-aspartate transporter (GLAST), Iba-1 and TMEM119 were used in the TN rat model by immunohistochemistry and flow cytometry. On the post operation day 28, GFAP/C3-positive A1 astrocytes and GFAP/S100A10-positive A2 astrocytes were activated in the TREZ after compression injury, there were no statistical differences in the ratios of A1/A2 astrocytes between the sham and TN groups. There was no significant difference in Iba-1-positive cells between the two groups. The ratios of infiltrating lymphocytes (CD45+CD11b−) (p = 0.0075) and infiltrating macrophages (CD45highCD11b+) (p = 0.0388) were significantly higher than those of the sham group. In conclusion, different subtypes A1/A2 astrocytes in the TREZ were activated after compression injury, infiltrating macrophages and lymphocytes increased, these neuroimmune cells in the TREZ may participate in the pathogenesis of TN rat model.
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Affiliation(s)
- Junjin Lin
- Public Technology Service Center of Fujian Medical University; Laboratory of Clinical Applied Anatomy, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, P.R. China
| | - Luxi Zhou
- Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, 350122, P.R. China.,Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P.R. China
| | - Zhaoke Luo
- Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, 350122, P.R. China.,Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P.R. China
| | - Madeha Ishag Adam
- Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, 350122, P.R. China.,Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P.R. China
| | - Li Zhao
- Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, 350122, P.R. China.,Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P.R. China
| | - Feng Wang
- Public Technology Service Center of Fujian Medical University; Laboratory of Clinical Applied Anatomy, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, P.R. China. .,Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, 350122, P.R. China. .,Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P.R. China.
| | - Daoshu Luo
- Public Technology Service Center of Fujian Medical University; Laboratory of Clinical Applied Anatomy, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, P.R. China. .,Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fuzhou, 350122, P.R. China. .,Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town, Fuzhou, 350122, P.R. China.
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