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 inFrontiers in cellular neuroscience Vol. 14; p. 185
Main Authors Lüningschrör, Patrick, Slotta, Carsten, Heimann, Peter, Briese, Michael, Weikert, Ulrich M., Massih, Bita, Appenzeller, Silke, Sendtner, Michael, Kaltschmidt, Christian, Kaltschmidt, Barbara
Format Journal Article
LanguageEnglish
Published Lausanne Frontiers Research Foundation 07.07.2020
Frontiers Media S.A
Subjects
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
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Summary: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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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
ISSN:1662-5102
1662-5102
DOI:10.3389/fncel.2020.00185