Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves
Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered as the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system, myelin can be degraded in an autophagy-dependent manner d...
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| Published in | Frontiers in cellular neuroscience Vol. 14; p. 185 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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07.07.2020
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| Abstract | Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered as the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system, myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) regulates both, Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs for demyelination and inflammation. Using RNAseq we unraveled a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4+ and CD8+ T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders. |
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| AbstractList | Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered as the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system, myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) regulates both, Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs for demyelination and inflammation. Using RNAseq we unraveled a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4+ and CD8+ T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders. Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4+ and CD8+ T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders. Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5 -deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5 -deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4 + and CD8 + T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders. |
| Author | Sendtner, Michael Appenzeller, Silke Massih, Bita Kaltschmidt, Christian Heimann, Peter Lüningschrör, Patrick Slotta, Carsten Weikert, Ulrich M Briese, Michael Kaltschmidt, Barbara |
| AuthorAffiliation | 4 Core Unit Systems Medicine, University of Wuerzburg , Wuerzburg , Germany 5 Comprehensive Cancer Center Mainfranken, University Hospital Wuerzburg , Wuerzburg , Germany 2 Department of Cell Biology, University of Bielefeld , Bielefeld , Germany 1 Institute of Clinical Neurobiology, University Hospital Wuerzburg , Wuerzburg , Germany 3 Molecular Neurobiology, University of Bielefeld , Bielefeld , Germany |
| AuthorAffiliation_xml | – name: 2 Department of Cell Biology, University of Bielefeld , Bielefeld , Germany – name: 3 Molecular Neurobiology, University of Bielefeld , Bielefeld , Germany – name: 5 Comprehensive Cancer Center Mainfranken, University Hospital Wuerzburg , Wuerzburg , Germany – name: 4 Core Unit Systems Medicine, University of Wuerzburg , Wuerzburg , Germany – name: 1 Institute of Clinical Neurobiology, University Hospital Wuerzburg , Wuerzburg , Germany |
| Author_xml | – sequence: 1 givenname: Patrick surname: Lüningschrör fullname: Lüningschrör, Patrick – sequence: 2 givenname: Carsten surname: Slotta fullname: Slotta, Carsten – sequence: 3 givenname: Peter surname: Heimann fullname: Heimann, Peter – sequence: 4 givenname: Michael surname: Briese fullname: Briese, Michael – sequence: 5 givenname: Ulrich M. surname: Weikert fullname: Weikert, Ulrich M. – sequence: 6 givenname: Bita surname: Massih fullname: Massih, Bita – sequence: 7 givenname: Silke surname: Appenzeller fullname: Appenzeller, Silke – sequence: 8 givenname: Michael surname: Sendtner fullname: Sendtner, Michael – sequence: 9 givenname: Christian surname: Kaltschmidt fullname: Kaltschmidt, Christian – sequence: 10 givenname: Barbara surname: Kaltschmidt fullname: Kaltschmidt, Barbara |
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| CitedBy_id | crossref_primary_10_1016_j_nmd_2021_06_004 crossref_primary_10_3389_fneur_2022_908148 crossref_primary_10_1111_ene_14752 |
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| ContentType | Journal Article |
| Copyright | 2020. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Copyright © 2020 Lüningschrör, Slotta, Heimann, Briese, Weikert, Massih, Appenzeller, Sendtner, Kaltschmidt and Kaltschmidt. 2020 Lüningschrör, Slotta, Heimann, Briese, Weikert, Massih, Appenzeller, Sendtner, Kaltschmidt and Kaltschmidt |
| Copyright_xml | – notice: 2020. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: Copyright © 2020 Lüningschrör, Slotta, Heimann, Briese, Weikert, Massih, Appenzeller, Sendtner, Kaltschmidt and Kaltschmidt. 2020 Lüningschrör, Slotta, Heimann, Briese, Weikert, Massih, Appenzeller, Sendtner, Kaltschmidt and Kaltschmidt |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: John Svaren, University of Wisconsin-Madison, United States; Douglas Fields, National Institutes of Health (NIH), United States; Ye Zhou, Regeneron Pharmaceuticals, Inc., United States Specialty section: This article was submitted to Non-Neuronal Cells, a section of the journal Frontiers in Cellular Neuroscience These authors have contributed equally to this work Edited by: Veronica Ines Brito, Vall d’Hebron University Hospital, Spain |
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| SubjectTerms | Autophagy CD4 antigen CD8 antigen Cellular Neuroscience Demyelination Homology Immune response Laboratory animals Lymphocytes T Macrophages Microscopy Myelin Nervous system Neurodegenerative diseases NF-κB protein Penicillin Peripheral nerves Phagocytosis Plasmids Pleckstrin PLEKHG5 Schwann cells Transcription |
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| Title | Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves |
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