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Wilkins JM, Mangalaparthi KK, Netzel BC, Sherman WA, Guo Y, Kalinowska-Lyszczarz A, Pandey A, Lucchinetti CF. Proteomics analysis of periplaque and chronic inactive multiple sclerosis lesions. Front Mol Neurosci 2024; 17:1448215. [PMID: 39234409 PMCID: PMC11371774 DOI: 10.3389/fnmol.2024.1448215] [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: 06/12/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Background Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by increased inflammation and immune responses, oxidative injury, mitochondrial dysfunction, and iron dyshomeostasis leading to demyelination and axonal damage. In MS, incomplete remyelination results in chronically demyelinated axons and degeneration coinciding with disability. This suggests a failure in the ability to remyelinate in MS, however, the precise underlying mechanisms remain unclear. We aimed to identify proteins whose expression was altered in chronic inactive white matter lesions and periplaque white matter in MS tissue to reveal potential pathophysiological mechanisms. Methods Laser capture microdissection coupled to proteomics was used to interrogate spatially altered changes in formalin-fixed paraffin-embedded brain tissue from three chronic MS individuals and three controls with no apparent neurological complications. Histopathological maps guided the capture of inactive lesions, periplaque white matter, and cortex from chronic MS individuals along with corresponding white matter and cortex from control tissue. Label free quantitation by liquid chromatography tandem mass spectrometry was used to discover differentially expressed proteins between the various brain regions. Results In addition to confirming loss of several myelin-associated proteins known to be affected in MS, proteomics analysis of chronic inactive MS lesions revealed alterations in myelin assembly, metabolism, and cytoskeletal organization. The top altered proteins in MS inactive lesions compared to control white matter consisted of PPP1R14A, ERMN, SIRT2, CARNS1, and MBLAC2. Conclusion Our findings highlight proteome changes in chronic inactive MS white matter lesions and periplaque white matter, which may be crucial for proper myelinogenesis, bioenergetics, focal adhesions, and cellular function. This study highlights the importance and feasibility of spatial approaches such as laser capture microdissection-based proteomics analysis of pathologically distinct regions of MS brain tissue. Identification of spatially resolved changes in the proteome of MS brain tissue should aid in the understanding of pathophysiological mechanisms and the development of novel therapies.
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Affiliation(s)
- Jordan M Wilkins
- Department of Neurology, Mayo Clinic, Rochester, MN, United States
| | - Kiran K Mangalaparthi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Brian C Netzel
- Department of Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN, United States
| | - William A Sherman
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Yong Guo
- Department of Neurology, Mayo Clinic, Rochester, MN, United States
| | - Alicja Kalinowska-Lyszczarz
- Department of Neurology, Division of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, Poznan, Poland
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Claudia F Lucchinetti
- Department of Neurology, The University of Texas at Austin, Austin, TX, United States
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2
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Donders Z, Skorupska IJ, Willems E, Mussen F, Broeckhoven JV, Carlier A, Schepers M, Vanmierlo T. Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system. Biomed Pharmacother 2024; 177:117009. [PMID: 38908196 DOI: 10.1016/j.biopha.2024.117009] [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: 03/28/2024] [Revised: 05/27/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024] Open
Abstract
Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown that increased cAMP levels in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating cAMP levels through PDE inhibition provides a therapeutic approach for multiple CNS disorders, including multiple sclerosis, stroke, spinal cord injury, amyotrophic lateral sclerosis, traumatic brain injury, and Alzheimer's disease. In particular, inhibition of the cAMP-specific PDE4 subfamily is widely studied because of its high expression in the CNS. So far, the clinical translation of full PDE4 inhibitors has been hampered because of dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon PDE4 inhibition presents a promising strategy, offering novel and pharmacologically safe targets for treating CNS disorders. Yet, the underlying downstream signaling pathways activated upon PDE(4) inhibition remain partially elusive. This review provides a comprehensive overview of the existing knowledge regarding downstream mediators of cAMP signaling induced by PDE4 inhibition or cAMP stimulators. Furthermore, we highlight existing gaps and future perspectives that may incentivize additional downstream research concerning PDE(4) inhibition, thereby providing novel therapeutic approaches for CNS disorders.
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Affiliation(s)
- Zoë Donders
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium
| | - Iga Joanna Skorupska
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium; Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht 6629ER, the Netherlands
| | - Emily Willems
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium
| | - Femke Mussen
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium
| | - Jana Van Broeckhoven
- Department of Immunology and Infection, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium; University MS Centre (UMSC) Hasselt - Pelt, Belgium
| | - Aurélie Carlier
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht 6629ER, the Netherlands
| | - Melissa Schepers
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium; University MS Centre (UMSC) Hasselt - Pelt, Belgium
| | - Tim Vanmierlo
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt 3500, Belgium; University MS Centre (UMSC) Hasselt - Pelt, Belgium.
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3
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Bonadio JD, Bashiri G, Halligan P, Kegel M, Ahmed F, Wang K. Delivery technologies for therapeutic targeting of fibronectin in autoimmunity and fibrosis applications. Adv Drug Deliv Rev 2024; 209:115303. [PMID: 38588958 PMCID: PMC11111362 DOI: 10.1016/j.addr.2024.115303] [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: 10/02/2023] [Revised: 02/29/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
Fibronectin (FN) is a critical component of the extracellular matrix (ECM) contributing to various physiological processes, including tissue repair and immune response regulation. FN regulates various cellular functions such as adhesion, proliferation, migration, differentiation, and cytokine release. Alterations in FN expression, deposition, and molecular structure can profoundly impact its interaction with other ECM proteins, growth factors, cells, and associated signaling pathways, thus influencing the progress of diseases such as fibrosis and autoimmune disorders. Therefore, developing therapeutics that directly target FN or its interaction with cells and other ECM components can be an intriguing approach to address autoimmune and fibrosis pathogenesis.
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Affiliation(s)
- Jacob D Bonadio
- Department of Bioengineering, Temple University, Philadelphia, PA, United States
| | - Ghazal Bashiri
- Department of Bioengineering, Temple University, Philadelphia, PA, United States
| | - Patrick Halligan
- Department of Bioengineering, Temple University, Philadelphia, PA, United States
| | - Michael Kegel
- Department of Bioengineering, Temple University, Philadelphia, PA, United States
| | - Fatima Ahmed
- Department of Bioengineering, Temple University, Philadelphia, PA, United States
| | - Karin Wang
- Department of Bioengineering, Temple University, Philadelphia, PA, United States.
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4
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Samtani G, Kim S, Michaud D, Hillhouse AE, Szule JA, Konganti K, Li J. Brain region dependent molecular signatures and myelin repair following chronic demyelination. Front Cell Neurosci 2023; 17:1169786. [PMID: 37180951 PMCID: PMC10171432 DOI: 10.3389/fncel.2023.1169786] [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: 02/20/2023] [Accepted: 04/03/2023] [Indexed: 05/16/2023] Open
Abstract
Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS.
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Affiliation(s)
- Grace Samtani
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, United States
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, United States
| | - Sunja Kim
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, United States
| | - Danielle Michaud
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, United States
| | - Andrew E. Hillhouse
- Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, United States
| | - Joseph A. Szule
- Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States
| | - Kranti Konganti
- Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, United States
| | - Jianrong Li
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, United States
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, United States
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5
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Zeng Y, Suo C, Yao S, Lu D, Larsson H, D'Onofrio BM, Lichtenstein P, Fang F, Valdimarsdóttir UA, Song H. Genetic Associations Between Stress-Related Disorders and Autoimmune Disease. Am J Psychiatry 2023; 180:294-304. [PMID: 37002690 DOI: 10.1176/appi.ajp.20220364] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
Objective: Emerging evidence supports a bidirectional phenotypic association between stress-related disorders and autoimmune disease. However, the biological underpinnings remain unclear. Here, the authors examined whether and how shared genetics contribute to the observed phenotypic associations. Methods: Based on data from 4,123,631 individuals identified from Swedish nationwide registers, familial coaggregation of stress-related disorders (any disorder or posttraumatic stress disorder [PTSD]) and autoimmune disease were initially estimated in seven cohorts with different degrees of kinship. Polygenic risk score (PRS) analyses were then performed with individual-level genotyping data from 376,871 participants in the UK Biobank study. Finally, genetic correlation analyses and enrichment analyses were performed with genome-wide association study (GWAS) summary statistics. Results: Familial coaggregation analyses revealed decreasing odds of concurrence of stress-related disorders and autoimmune disease with descending kinship or genetic relatedness between pairs of relatives; adjusted odds ratios were 1.51 (95% CI=1.09–2.07), 1.28 (95% CI=0.97–1.68), 1.16 (95% CI=1.14–1.18), and 1.01 (95% CI=0.98–1.03) for monozygotic twins, dizygotic twins, full siblings, and half cousins, respectively. Statistically significant positive associations were observed between PRSs of stress-related disorders and autoimmune disease, as well as between PRSs of autoimmune disease and stress-related disorders. GWAS summary statistics revealed a genetic correlation of 0.26 (95% CI=0.14–0.38) between these two phenotypes and identified 10 common genes and five shared functional modules, including one module related to G-protein–coupled receptor pathways. Similar analyses performed for PTSD and specific autoimmune diseases (e.g., autoimmune thyroid disease) largely recapitulated the results of the main analyses. Conclusions: This study demonstrated familial coaggregation, genetic correlation, and common biological pathways between stress-related disorders and autoimmune disease.
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Affiliation(s)
- Yu Zeng
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Chen Suo
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Shuyang Yao
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Donghao Lu
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Henrik Larsson
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Brian M D'Onofrio
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Paul Lichtenstein
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Fang Fang
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Unnur A Valdimarsdóttir
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
| | - Huan Song
- West China Biomedical Big Data Center, West China Hospital (Zeng, Lu, Fang, Song), and Med-X Center for Informatics (Zeng, Song), Sichuan University, Chengdu, China; Department of Epidemiology and Ministry of Education Key Laboratory of Public Health Safety, School of Public Health, Fudan University, Shanghai (Suo); Department of Medical Epidemiology and Biostatistics (Yao, Larsson, D'Onofrio, Lichtenstein) and Institute of Environmental Medicine (Lu, Fang, Valdimarsdóttir), Karolinska Institutet, Stockholm; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Lu, Valdimarsdóttir); School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Psychological and Brain Sciences, Indiana University, Bloomington (D'Onofrio); Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík (Valdimarsdóttir, Song)
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6
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Schepers M, Paes D, Tiane A, Rombaut B, Piccart E, van Veggel L, Gervois P, Wolfs E, Lambrichts I, Brullo C, Bruno O, Fedele E, Ricciarelli R, Ffrench-Constant C, Bechler ME, van Schaik P, Baron W, Lefevere E, Wasner K, Grünewald A, Verfaillie C, Baeten P, Broux B, Wieringa P, Hellings N, Prickaerts J, Vanmierlo T. Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis. Brain Behav Immun 2023; 109:1-22. [PMID: 36584795 DOI: 10.1016/j.bbi.2022.12.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/17/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS.
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Affiliation(s)
- Melissa Schepers
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium
| | - Dean Paes
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Assia Tiane
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium
| | - Ben Rombaut
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Elisabeth Piccart
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
| | - Lieve van Veggel
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium
| | - Pascal Gervois
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Esther Wolfs
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Department of Cardio and Organ Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Chiara Brullo
- Department of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Genova, Italy
| | - Olga Bruno
- Department of Pharmacy, Section of Medicinal Chemistry, University of Genoa, Genova, Italy
| | - Ernesto Fedele
- Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Roberta Ricciarelli
- IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Experimental Medicine, Section of General Pathology, University of Genova, Genova, Italy
| | - Charles Ffrench-Constant
- MRC Centre for Regenerative Medicine and MS Society Edinburgh Centre, Edinburgh bioQuarter, University of Edinburgh, Edinburgh, UK
| | - Marie E Bechler
- Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Pauline van Schaik
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Wia Baron
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Evy Lefevere
- Rewind Therapeutics NV, Gaston Geenslaan 2, B-3001, Leuven, Belgium
| | - Kobi Wasner
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Anne Grünewald
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Catherine Verfaillie
- Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Belgium
| | - Paulien Baeten
- University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Bieke Broux
- University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Paul Wieringa
- MERLN Institute for Technology-Inspired Regenerative Medicine, Complex Tissue Regeneration department, Maastricht University, Maastricht, the Netherlands
| | - Niels Hellings
- University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium; Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jos Prickaerts
- Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Tim Vanmierlo
- Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium.
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7
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Ping J, Fu H, Xiong YJ, Soomro S, Huang ZH, Yu PP. Poly-L-ornithine blocks the inhibitory effects of fibronectin on oligodendrocyte differentiation and promotes myelin repair. Neural Regen Res 2023; 18:832-839. [DOI: 10.4103/1673-5374.353493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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8
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Vasques J, de Jesus Gonçalves R, da Silva-Junior A, Martins R, Gubert F, Mendez-Otero R. Gangliosides in nervous system development, regeneration, and pathologies. Neural Regen Res 2023. [PMID: 35799513 PMCID: PMC9241395 DOI: 10.4103/1673-5374.343890] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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9
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Leo H, Kipp M. Remyelination in Multiple Sclerosis: Findings in the Cuprizone Model. Int J Mol Sci 2022; 23:ijms232416093. [PMID: 36555733 PMCID: PMC9783537 DOI: 10.3390/ijms232416093] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Remyelination therapies, which are currently under development, have a great potential to delay, prevent or even reverse disability in multiple sclerosis patients. Several models are available to study the effectiveness of novel compounds in vivo, among which is the cuprizone model. This model is characterized by toxin-induced demyelination, followed by endogenous remyelination after cessation of the intoxication. Due to its high reproducibility and ease of use, this model enjoys high popularity among various research and industrial groups. In this review article, we will summarize recent findings using this model and discuss the potential of some of the identified compounds to promote remyelination in multiple sclerosis patients.
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Affiliation(s)
| | - Markus Kipp
- Correspondence: ; Tel.: +49-(0)-381-494-8400
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10
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van Schaik PEM, Zuhorn IS, Baron W. Targeting Fibronectin to Overcome Remyelination Failure in Multiple Sclerosis: The Need for Brain- and Lesion-Targeted Drug Delivery. Int J Mol Sci 2022; 23:8418. [PMID: 35955549 PMCID: PMC9368816 DOI: 10.3390/ijms23158418] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 11/16/2022] Open
Abstract
Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease with unknown etiology that can be characterized by the presence of demyelinated lesions. Prevailing treatment protocols in MS rely on the modulation of the inflammatory process but do not impact disease progression. Remyelination is an essential factor for both axonal survival and functional neurological recovery but is often insufficient. The extracellular matrix protein fibronectin contributes to the inhibitory environment created in MS lesions and likely plays a causative role in remyelination failure. The presence of the blood-brain barrier (BBB) hinders the delivery of remyelination therapeutics to lesions. Therefore, therapeutic interventions to normalize the pathogenic MS lesion environment need to be able to cross the BBB. In this review, we outline the multifaceted roles of fibronectin in MS pathogenesis and discuss promising therapeutic targets and agents to overcome fibronectin-mediated inhibition of remyelination. In addition, to pave the way for clinical use, we reflect on opportunities to deliver MS therapeutics to lesions through the utilization of nanomedicine and discuss strategies to deliver fibronectin-directed therapeutics across the BBB. The use of well-designed nanocarriers with appropriate surface functionalization to cross the BBB and target the lesion sites is recommended.
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Affiliation(s)
- Pauline E. M. van Schaik
- Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;
| | - Inge S. Zuhorn
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
| | - Wia Baron
- Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands;
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11
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Podbielska M, Ariga T, Pokryszko-Dragan A. Sphingolipid Players in Multiple Sclerosis: Their Influence on the Initiation and Course of the Disease. Int J Mol Sci 2022; 23:ijms23105330. [PMID: 35628142 PMCID: PMC9140914 DOI: 10.3390/ijms23105330] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/05/2022] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Sphingolipids (SLs) play a significant role in the nervous system, as major components of the myelin sheath, contributors to lipid raft formation that organize intracellular processes, as well as active mediators of transport, signaling and the survival of neurons and glial cells. Alterations in SL metabolism and content are observed in the course of central nervous system diseases, including multiple sclerosis (MS). In this review, we summarize the current evidence from studies on SLs (particularly gangliosides), which may shed new light upon processes underlying the MS background. The relevant aspects of these studies include alterations of the SL profile in MS, the role of antibodies against SLs and complexes of SL-ligand-invariant NKT cells in the autoimmune response as the core pathomechanism in MS. The contribution of lipid-raft-associated SLs and SL-laden extracellular vesicles to the disease etiology is also discussed. These findings may have diagnostic implications, with SLs and anti-SL antibodies as potential markers of MS activity and progression. Intriguing prospects of novel therapeutic options in MS are associated with SL potential for myelin repair and neuroprotective effects, which have not been yet addressed by the available treatment strategies. Overall, all these concepts are promising and encourage the further development of SL-based studies in the field of MS.
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Affiliation(s)
- Maria Podbielska
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
- Laboratory of Microbiome Immunobiology, Ludwik Hirszfeld Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
- Correspondence: ; Tel.: +48-71-370-99-12
| | - Toshio Ariga
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
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12
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Allanach JR, Farrell JW, Mésidor M, Karimi-Abdolrezaee S. Current status of neuroprotective and neuroregenerative strategies in multiple sclerosis: A systematic review. Mult Scler 2022; 28:29-48. [PMID: 33870797 PMCID: PMC8688986 DOI: 10.1177/13524585211008760] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 03/13/2021] [Accepted: 03/21/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Immune-mediated demyelination and consequent degeneration of oligodendrocytes and axons are hallmark features of multiple sclerosis (MS). Remyelination declines in progressive MS, causing permanent axonal loss and irreversible disabilities. Strategies aimed at enhancing remyelination are critical to attenuate disease progression. OBJECTIVE We systematically reviewed recent advances in neuroprotective and regenerative therapies for MS, covering preclinical and clinical studies. METHODS We searched three biomedical databases using defined keywords. Two authors independently reviewed articles for inclusion based on pre-specified criteria. The data were extracted from each study and assessed for risk of bias. RESULTS Our search identified 7351 studies from 2014 to 2020, of which 221 met the defined criteria. These studies reported 262 interventions, wherein 92% were evaluated in animal models. These interventions comprised protein, RNA, lipid and cellular biologics, small molecules, inorganic compounds, and dietary and physiological interventions. Small molecules were the most highly represented strategy, followed by antibody therapies and stem cell transplantation. CONCLUSION While significant strides have been made to develop regenerative treatments for MS, the current evidence illustrates a skewed representation of the types of strategies that advance to clinical trials. Further examination is thus required to address current barriers to implementing experimental treatments in clinical settings.
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Affiliation(s)
- Jessica R Allanach
- Department of Microbiology and Immunology, The University of British Columbia, Vancouver, BC, Canada
| | - John W. Farrell
- Department of Health and Human Performance, Texas State University, San Marcos, TX, USA
| | - Miceline Mésidor
- Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada/Department of Social and Preventive Medicine, Université de Montréal, Montréal, QC, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada/Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
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13
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Gorter RP, Dijksman NS, Baron W, Colognato H. Investigating demyelination, efficient remyelination and remyelination failure in organotypic cerebellar slice cultures: Workflow and practical tips. Methods Cell Biol 2022; 168:103-123. [DOI: 10.1016/bs.mcb.2021.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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14
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Ghorbani S, Yong VW. The extracellular matrix as modifier of neuroinflammation and remyelination in multiple sclerosis. Brain 2021; 144:1958-1973. [PMID: 33889940 PMCID: PMC8370400 DOI: 10.1093/brain/awab059] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Remyelination failure contributes to axonal loss and progression of disability in multiple sclerosis. The failed repair process could be due to ongoing toxic neuroinflammation and to an inhibitory lesion microenvironment that prevents recruitment and/or differentiation of oligodendrocyte progenitor cells into myelin-forming oligodendrocytes. The extracellular matrix molecules deposited into lesions provide both an altered microenvironment that inhibits oligodendrocyte progenitor cells, and a fuel that exacerbates inflammatory responses within lesions. In this review, we discuss the extracellular matrix and where its molecules are normally distributed in an uninjured adult brain, specifically at the basement membranes of cerebral vessels, in perineuronal nets that surround the soma of certain populations of neurons, and in interstitial matrix between neural cells. We then highlight the deposition of different extracellular matrix members in multiple sclerosis lesions, including chondroitin sulphate proteoglycans, collagens, laminins, fibronectin, fibrinogen, thrombospondin and others. We consider reasons behind changes in extracellular matrix components in multiple sclerosis lesions, mainly due to deposition by cells such as reactive astrocytes and microglia/macrophages. We next discuss the consequences of an altered extracellular matrix in multiple sclerosis lesions. Besides impairing oligodendrocyte recruitment, many of the extracellular matrix components elevated in multiple sclerosis lesions are pro-inflammatory and they enhance inflammatory processes through several mechanisms. However, molecules such as thrombospondin-1 may counter inflammatory processes, and laminins appear to favour repair. Overall, we emphasize the crosstalk between the extracellular matrix, immune responses and remyelination in modulating lesions for recovery or worsening. Finally, we review potential therapeutic approaches to target extracellular matrix components to reduce detrimental neuroinflammation and to promote recruitment and maturation of oligodendrocyte lineage cells to enhance remyelination.
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Affiliation(s)
- Samira Ghorbani
- Hotchkiss Brain Institute and the Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada
| | - V Wee Yong
- Hotchkiss Brain Institute and the Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada
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15
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Werkman IL, Kövilein J, de Jonge JC, Baron W. Impairing committed cholesterol biosynthesis in white matter astrocytes, but not grey matter astrocytes, enhances in vitro myelination. J Neurochem 2021; 156:624-641. [PMID: 32602556 PMCID: PMC7984098 DOI: 10.1111/jnc.15113] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/20/2020] [Accepted: 06/12/2020] [Indexed: 12/20/2022]
Abstract
Remyelination is a regenerative process that is essential to recover saltatory conduction and to prevent neurodegeneration upon demyelination. The formation of new myelin involves the differentiation of oligodendrocyte progenitor cells (OPCs) toward oligodendrocytes and requires high amounts of cholesterol. Astrocytes (ASTRs) modulate remyelination by supplying lipids to oligodendrocytes. Remarkably, remyelination is more efficient in grey matter (GM) than in white matter (WM), which may relate to regional differences in ASTR subtype. Here, we show that a feeding layer of gmASTRs was more supportive to in vitro myelination than a feeding layer of wmASTRs. While conditioned medium from both gmASTRs and wmASTRs accelerated gmOPC differentiation, wmOPC differentiation is enhanced by secreted factors from gmASTRs, but not wmASTRs. In vitro analyses revealed that gmASTRs secreted more cholesterol than wmASTRs. Cholesterol efflux from both ASTR types was reduced upon exposure to pro-inflammatory cytokines, which was mediated via cholesterol transporter ABCA1, but not ABCG1, and correlated with a minor reduction of myelin membrane formation by oligodendrocytes. Surprisingly, a wmASTR knockdown of Fdft1 encoding for squalene synthase (SQS), an enzyme essential for the first committed step in cholesterol biosynthesis, enhanced in vitro myelination. Reduced secretion of interleukin-1β likely by enhanced isoprenylation, and increased unsaturated fatty acid synthesis, both pathways upstream of SQS, likely masked the effect of reduced levels of ASTR-derived cholesterol. Hence, our findings indicate that gmASTRs export more cholesterol and are more supportive to myelination than wmASTRs, but specific inhibition of cholesterol biosynthesis in ASTRs is beneficial for wmASTR-mediated modulation of myelination.
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Affiliation(s)
- Inge L. Werkman
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
- Present address:
Department of BiologyUniversity of VirginiaCharlottesvilleVAUSA
| | - Janine Kövilein
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Jenny C. de Jonge
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Wia Baron
- Biomedical Sciences of Cells & Systemssection Molecular NeurobiologyUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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16
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Su M, Soomro SH, Jie J, Fu H. Effects of the extracellular matrix on myelin development and regeneration in the central nervous system. Tissue Cell 2021; 69:101444. [PMID: 33450651 DOI: 10.1016/j.tice.2020.101444] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/23/2020] [Accepted: 10/05/2020] [Indexed: 12/25/2022]
Abstract
Extracellular matrix (ECM) is a collection of extracellular molecules secreted by cells, providing structural and biochemical support for surrounding tissues. The ECM exerts biological effects by interacting with growth factors, signal receptors or adhesion molecules. In the case of myelin formation and regeneration, the combination of ECM and its receptors (for example, integrins) modulates signaling pathways such as PI3K, MAPK, etc., which in turn induces complex biological effects throughout various stages of myelination and regeneration. Studies have also found that myelin injury would cause changes in ECM composition and thus affecting the myelin regeneration process. Research on the ECM will provide a better understanding of how myelin is formed and regenerated, which will help to develop new therapies for demyelinating diseases. Future progress in this field will provide important information on how to modify the ECM to promote proliferation and differentiation of oligodendrocyte precursor cells (OPC), thereby stimulating myelin formation and regeneration and restoring normal neural function.
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Affiliation(s)
- Min Su
- Wuhan University, School of Basic Medical Sciences, Wuhan, China.
| | | | - Jifu Jie
- Health School of Bayinguoleng Mongolian Autonomous Prefecture, Xinjiang, China.
| | - Hui Fu
- Wuhan University, School of Basic Medical Sciences, Wuhan, China.
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17
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Nowack L, Teschers CS, Albrecht S, Gilmour R. Oligodendroglial glycolipids in (Re)myelination: implications for multiple sclerosis research. Nat Prod Rep 2021; 38:890-904. [PMID: 33575689 DOI: 10.1039/d0np00093k] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Covering: up to 2020 This short review surveys aspects of glycolipid-based natural products and their biological relevance in multiple sclerosis (MS). The role of isolated gangliosides in disease models is discussed together with an overview of ganglioside-inspired small molecule drugs and imaging probes. The discussion is extended to neurodegeneration in a more general context and addresses the need for more efficient synthetic methods to generate (glyco)structures that are of therapeutic relevance.
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Affiliation(s)
- Luise Nowack
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany. and Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany.
| | - Charlotte S Teschers
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany.
| | - Stefanie Albrecht
- Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany.
| | - Ryan Gilmour
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany.
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18
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Werkman IL, Dubbelaar ML, van der Vlies P, de Boer-Bergsma JJ, Eggen BJL, Baron W. Transcriptional heterogeneity between primary adult grey and white matter astrocytes underlie differences in modulation of in vitro myelination. J Neuroinflammation 2020; 17:373. [PMID: 33308248 PMCID: PMC7733297 DOI: 10.1186/s12974-020-02045-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 11/25/2020] [Indexed: 12/31/2022] Open
Abstract
Background Multiple sclerosis (MS) is an inflammation-mediated demyelinating disease of the central nervous system that eventually results in secondary axonal degeneration due to remyelination failure. Successful remyelination is orchestrated by astrocytes (ASTRs) and requires sequential activation, recruitment, and maturation of oligodendrocyte progenitor cells (OPCs). In both MS and experimental models, remyelination is more robust in grey matter (GM) than white matter (WM), which is likely related to local differences between GM and WM lesions. Here, we investigated whether adult gmASTRs and wmASTRs per se and in response to MS relevant Toll-like receptor (TLR) activation differently modulate myelination. Methods Differences in modulation of myelination between adult gmASTRs and wmASTRs were examined using an in vitro myelinating system that relies on a feeding layer of ASTRs. Transcriptional profiling and weighted gene co-expression network analysis were used to analyze differentially expressed genes and gene networks. Potential differential modulation of OPC proliferation and maturation by untreated adult gmASTRs and wmASTRs and in response to TLR3 and TLR4 agonists were assessed. Results Our data reveal that adult wmASTRs are less supportive to in vitro myelination than gmASTRs. WmASTRs more abundantly express reactive ASTR genes and genes of a neurotoxic subtype of ASTRs, while gmASTRs have more neuro-reparative transcripts. We identified a gene network module containing cholesterol biosynthesis enzyme genes that positively correlated with gmASTRs, and a network module containing extracellular matrix-related genes that positively correlated with wmASTRs. Adult wmASTRs and gmASTRs responding to TLR3 agonist Poly(I:C) distinctly modulate OPC behavior, while exposure to TLR4 agonist LPS of both gmASTRs and wmASTRs results in a prominent decrease in myelin membrane formation. Conclusions Primary adult gmASTRs and wmASTRs are heterogeneous at the transcriptional level, differed in their support of in vitro myelination, and their pre-existing phenotype determined TLR3 agonist responses. These findings point to a role of ASTR heterogeneity in regional differences in remyelination efficiency between GM and WM lesions. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-020-02045-3.
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Affiliation(s)
- Inge L Werkman
- Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713, AV, Groningen, the Netherlands
| | - Marissa L Dubbelaar
- Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713, AV, Groningen, the Netherlands
| | - Pieter van der Vlies
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jelkje J de Boer-Bergsma
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bart J L Eggen
- Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713, AV, Groningen, the Netherlands
| | - Wia Baron
- Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713, AV, Groningen, the Netherlands.
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19
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Sipione S, Monyror J, Galleguillos D, Steinberg N, Kadam V. Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications. Front Neurosci 2020; 14:572965. [PMID: 33117120 PMCID: PMC7574889 DOI: 10.3389/fnins.2020.572965] [Citation(s) in RCA: 189] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/31/2020] [Indexed: 12/12/2022] Open
Abstract
Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.
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Affiliation(s)
- Simonetta Sipione
- Department of Pharmacology, Faculty of Medicine and Dentistry, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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20
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Ormstad H, Simonsen CS, Broch L, Maes DM, Anderson G, Celius EG. Chronic fatigue and depression due to multiple sclerosis: Immune-inflammatory pathways, tryptophan catabolites and the gut-brain axis as possible shared pathways. Mult Scler Relat Disord 2020; 46:102533. [PMID: 33010585 DOI: 10.1016/j.msard.2020.102533] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/03/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023]
Abstract
Chronic fatigue and major depression (MDD)-like symptoms are common manifestations of multiple sclerosis (MS), both with huge impact on quality of life. Depression can manifest itself as fatigue, and depressive symptoms are often mistaken for fatigue, and vice versa. The two conditions are sometimes difficult to differentiate, and their relationship is unclear. Whether chronic fatigue and depression occur primarily, secondarily or coincidentally with activated immune-inflammatory pathways in MS is still under debate. We have carried out a descriptive review aiming to gain a deeper understanding of the relationship between chronic fatigue and depression in MS, and the shared pathways that underpin both conditions. This review focuses on immune-inflammatory pathways, the kynurenine pathway and the gut-brain axis. It seems likely that proinflammatory cytokines, tryptophan catabolites (the KYN pathway) and the gut-brain axis are involved in the mechanisms causing chronic fatigue and MDD-like symptoms in MS. However, the evidence base is weak, and more research is needed. In order to advance our understanding of the underlying pathological mechanisms, MS-related fatigue and depression should be examined using a longitudinal design and both immune-inflammatory and KYN pathway biomarkers should be measured, relevant clinical characteristics judiciously registered, and self-report instruments for both fatigue and depression should be used.
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Affiliation(s)
- Heidi Ormstad
- University of South-Eastern Norway and University Oslo Metropolitan University.
| | | | | | - Dr Michael Maes
- Chulalongkorn University, Bangkok, Thailand; Medical University of Plovdiv, Plovdiv, Bulgaria; IMPACT Strategic Center, Deakin University, Australia
| | - George Anderson
- CRC Scotland & London, Eccleston Square, London, United Kingdom
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21
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Marangon D, Boccazzi M, Lecca D, Fumagalli M. Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair. J Clin Med 2020; 9:E470. [PMID: 32046349 PMCID: PMC7073561 DOI: 10.3390/jcm9020470] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/30/2020] [Accepted: 02/04/2020] [Indexed: 12/12/2022] Open
Abstract
: Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination.
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de Jong JM, Wang P, Oomkens M, Baron W. Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure). J Neurosci Res 2020; 98:1370-1397. [PMID: 31965607 DOI: 10.1002/jnr.24582] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/29/2019] [Accepted: 12/20/2019] [Indexed: 12/11/2022]
Abstract
The extracellular matrix (ECM) provides protection, rigidity, and structure toward cells. It consists, among others, of a wide variety of glycoproteins and proteoglycans, which act together to produce a complex and dynamic environment, most relevant in transmembrane events. In the brain, the ECM occupies a notable proportion of its volume and maintains the homeostasis of central nervous system (CNS). In addition, remodeling of the ECM, that is transient changes in ECM proteins regulated by matrix metalloproteinases (MMPs), is an important process that modulates cell behavior upon injury, thereby facilitating recovery. Failure of ECM remodeling plays an important role in the pathogenesis of multiple sclerosis (MS), a neurodegenerative demyelinating disease of the CNS with an inflammatory response against protective myelin sheaths that surround axons. Remyelination of denuded axons improves the neuropathological conditions of MS, but this regeneration process fails over time, leading to chronic disease progression. In this review, we uncover abnormal ECM remodeling in MS lesions by discussing ECM remodeling in experimental demyelination models, that is when remyelination is successful, and compare alterations in ECM components to the ECM composition and MMP expression in the parenchyma of demyelinated MS lesions, that is when remyelination fails. Inter- and intralesional differences in ECM remodeling in the distinct white matter MS lesions are discussed in terms of consequences for oligodendrocyte behavior and remyelination (failure). Hence, the review will aid to understand how abnormal ECM remodeling contributes to remyelination failure in MS lesions and assists in developing therapeutic strategies to promote remyelination.
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Affiliation(s)
- Jody M de Jong
- Section Molecular Neurobiology, Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Peng Wang
- Section Molecular Neurobiology, Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Michelle Oomkens
- Section Molecular Neurobiology, Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Wia Baron
- Section Molecular Neurobiology, Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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TLR3 agonists induce fibronectin aggregation by activated astrocytes: a role of pro-inflammatory cytokines and fibronectin splice variants. Sci Rep 2020; 10:532. [PMID: 31953424 PMCID: PMC6969115 DOI: 10.1038/s41598-019-57069-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 12/21/2019] [Indexed: 01/01/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system which eventually results in axonal loss mainly due to failure of remyelination. Previously we have shown that the persistent presence of stable astrocyte-derived fibronectin aggregates in MS lesions impairs OPC differentiation, and thereby remyelination. Here we set out to discern whether and, if so, how inflammatory mediators as present in MS lesions trigger astrocytes to form fibronectin aggregates. Our findings revealed that in slice cultures only upon demyelination, the TLR3 agonist Poly(I:C) evoked astrocytes to form fibronectin aggregates. Consistently, pro-inflammatory cytokine-pretreated astrocytes were more susceptible to Poly(I:C)-induced fibronectin aggregation, indicating that astrocytes form fibronectin aggregates upon a double hit by inflammatory mediators. The underlying mechanism involves disrupted fibronectin fibrillogenesis at the cell surface as a result of a cytokine-induced increase in relative mRNA levels of EIIIApos-Fn over EIIIBpos-Fn and a Poly(I:C)-mediated decrease in integrin affinity. Remarkably, fibronectin aggregation is exacerbated by white matter astrocytes compared to grey matter astrocytes, which may be a reflection of higher expression levels of EIIIApos-fibronectin in white matter astrocytes. Hence, interfering with alternative fibronectin splicing and/or TLR3-mediated signaling may prevent fibronectin aggregation and overcome remyelination failure in MS lesions.
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Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells. Int J Mol Sci 2019; 20:ijms20215500. [PMID: 31694154 PMCID: PMC6862663 DOI: 10.3390/ijms20215500] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 10/30/2019] [Accepted: 11/04/2019] [Indexed: 12/24/2022] Open
Abstract
Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.
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Acute and chronic demyelinated CNS lesions exhibit opposite elastic properties. Sci Rep 2019; 9:999. [PMID: 30700777 PMCID: PMC6354022 DOI: 10.1038/s41598-018-37745-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 12/07/2018] [Indexed: 01/07/2023] Open
Abstract
Increased deposition of extracellular matrix (ECM) is a known inhibitor of axonal regrowth and remyelination. Recent in vitro studies have demonstrated that oligodendrocyte differentiation is impacted by the physical properties of the ECM. However, characterization of the mechanical properties of the healthy and injured CNS myelin is challenging, and has largely relied on non-invasive, low-resolution methods. To address this, we have employed atomic force microscopy to perform micro-indentation measurements of demyelinated tissue at cellular scale. Analysis of mouse and human demyelinated brains indicate that acute demyelination results in decreased tissue stiffness that recovers with remyelination; while chronic demyelination is characterized by increased tissue stiffness, which correlates with augmented ECM deposition. Thus, changes in the mechanical properties of the acutely (softer) or chronically (stiffer) demyelinated brain might contribute to differences in their regenerative capacity. Our findings are relevant to the optimization of cell-based therapies aimed at promoting CNS regeneration and remyelination.
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Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer's Disease. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1483791. [PMID: 30112360 PMCID: PMC6077677 DOI: 10.1155/2018/1483791] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/19/2018] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) and multiple sclerosis are major neurodegenerative diseases, which are characterized by the accumulation of abnormal pathogenic proteins due to oxidative stress, mitochondrial dysfunction, impaired autophagy, and pathogens, leading to neurodegeneration and behavioral deficits. Herein, we reviewed the utility of plant polyphenols in regulating proliferation and differentiation of stem cells for inducing brain self-repair in AD and multiple sclerosis. Firstly, we discussed the genetic, physiological, and environmental factors involved in the pathophysiology of both the disorders. Next, we reviewed various stem cell therapies available and how they have proved useful in animal models of AD and multiple sclerosis. Lastly, we discussed how polyphenols utilize the potential of stem cells, either complementing their therapeutic effects or stimulating endogenous and exogenous neurogenesis, against these diseases. We suggest that polyphenols could be a potential candidate for stem cell therapy against neurodegenerative disorders.
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Kieser TJ, Santschi N, Nowack L, Kehr G, Kuhlmann T, Albrecht S, Gilmour R. Single Site Fluorination of the GM 4 Ganglioside Epitope Upregulates Oligodendrocyte Differentiation. ACS Chem Neurosci 2018; 9:1159-1165. [PMID: 29361218 DOI: 10.1021/acschemneuro.8b00002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Relapsing multiple sclerosis is synonymous with demyelination, and thus, suppressing and or reversing this process is of paramount clinical significance. While insulating myelin sheath has a large lipid composition (ca. 70-80%), it also has a characteristically large composition of the sialosylgalactosylceramide gangliosde GM4 present. In this study, the effect of the carbohydrate epitope on oligodendrocyte differentiation is determined. While the native epitope had no impact on oligodendroglial cell viability, a single site OH → F substitution is the structural basis of a significant increase in ATP production that is optimal at 50 μg/mL. From a translational perspective, this subtle change increases the amount of MBP+ oligodendrocytes compared to the control studies and may open up novel therapeutic remyelination strategies.
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Affiliation(s)
- Tobias J. Kieser
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
- Excellence Cluster EXC 1003 “Cells in Motion”, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
| | - Nico Santschi
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
- Excellence Cluster EXC 1003 “Cells in Motion”, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
| | - Luise Nowack
- Institute for Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany
| | - Gerald Kehr
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
| | - Tanja Kuhlmann
- Institute for Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany
| | - Stefanie Albrecht
- Institute for Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany
| | - Ryan Gilmour
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
- Excellence Cluster EXC 1003 “Cells in Motion”, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
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The Extracellular Matrix and Remyelination Strategies in Multiple Sclerosis. eNeuro 2018; 5:eN-COM-0435-17. [PMID: 29662941 PMCID: PMC5898789 DOI: 10.1523/eneuro.0435-17.2018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 01/31/2018] [Accepted: 02/16/2018] [Indexed: 12/29/2022] Open
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29
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The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies. Glia 2018; 66:1809-1825. [DOI: 10.1002/glia.23333] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 03/06/2018] [Accepted: 03/06/2018] [Indexed: 12/31/2022]
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