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Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation

Nodes of Ranvier and associated paranodal and juxtaparanodal domains along myelinated axons are essential for normal function of the peripheral and central nervous systems. Disruption of these domains as well as increases in the reactive carbonyl species methylglyoxal are implicated as a pathophysio...

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Autores principales: Griggs, Ryan B., Yermakov, Leonid M., Drouet, Domenica E., Nguyen, Duc V.M., Susuki, Keiichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944142/
https://www.ncbi.nlm.nih.gov/pubmed/29673258
http://dx.doi.org/10.1177/1759091418766175
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author Griggs, Ryan B.
Yermakov, Leonid M.
Drouet, Domenica E.
Nguyen, Duc V.M.
Susuki, Keiichiro
author_facet Griggs, Ryan B.
Yermakov, Leonid M.
Drouet, Domenica E.
Nguyen, Duc V.M.
Susuki, Keiichiro
author_sort Griggs, Ryan B.
collection PubMed
description Nodes of Ranvier and associated paranodal and juxtaparanodal domains along myelinated axons are essential for normal function of the peripheral and central nervous systems. Disruption of these domains as well as increases in the reactive carbonyl species methylglyoxal are implicated as a pathophysiology common to a wide variety of neurological diseases. Here, using an ex vivo nerve exposure model, we show that increasing methylglyoxal produces paranodal disruption, evidenced by disorganized immunostaining of axoglial cell-adhesion proteins, in both sciatic and optic nerves from wild-type mice. Consistent with previous studies showing that increase of methylglyoxal can alter intracellular calcium homeostasis, we found upregulated activity of the calcium-activated protease calpain in sciatic nerves after methylglyoxal exposure. Methylglyoxal exposure altered clusters of proteins that are known as calpain substrates: ezrin in Schwann cell microvilli at the perinodal area and zonula occludens 1 in Schwann cell autotypic junctions at paranodes. Finally, treatment with the calpain inhibitor calpeptin ameliorated methylglyoxal-evoked ezrin loss and paranodal disruption in both sciatic and optic nerves. Our findings strongly suggest that elevated methylglyoxal levels and subsequent calpain activation contribute to the disruption of specialized axoglial domains along myelinated nerve fibers in neurological diseases.
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spelling pubmed-59441422018-05-14 Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation Griggs, Ryan B. Yermakov, Leonid M. Drouet, Domenica E. Nguyen, Duc V.M. Susuki, Keiichiro ASN Neuro Original Paper Nodes of Ranvier and associated paranodal and juxtaparanodal domains along myelinated axons are essential for normal function of the peripheral and central nervous systems. Disruption of these domains as well as increases in the reactive carbonyl species methylglyoxal are implicated as a pathophysiology common to a wide variety of neurological diseases. Here, using an ex vivo nerve exposure model, we show that increasing methylglyoxal produces paranodal disruption, evidenced by disorganized immunostaining of axoglial cell-adhesion proteins, in both sciatic and optic nerves from wild-type mice. Consistent with previous studies showing that increase of methylglyoxal can alter intracellular calcium homeostasis, we found upregulated activity of the calcium-activated protease calpain in sciatic nerves after methylglyoxal exposure. Methylglyoxal exposure altered clusters of proteins that are known as calpain substrates: ezrin in Schwann cell microvilli at the perinodal area and zonula occludens 1 in Schwann cell autotypic junctions at paranodes. Finally, treatment with the calpain inhibitor calpeptin ameliorated methylglyoxal-evoked ezrin loss and paranodal disruption in both sciatic and optic nerves. Our findings strongly suggest that elevated methylglyoxal levels and subsequent calpain activation contribute to the disruption of specialized axoglial domains along myelinated nerve fibers in neurological diseases. SAGE Publications 2018-04-20 /pmc/articles/PMC5944142/ /pubmed/29673258 http://dx.doi.org/10.1177/1759091418766175 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Paper
Griggs, Ryan B.
Yermakov, Leonid M.
Drouet, Domenica E.
Nguyen, Duc V.M.
Susuki, Keiichiro
Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation
title Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation
title_full Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation
title_fullStr Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation
title_full_unstemmed Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation
title_short Methylglyoxal Disrupts Paranodal Axoglial Junctions via Calpain Activation
title_sort methylglyoxal disrupts paranodal axoglial junctions via calpain activation
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944142/
https://www.ncbi.nlm.nih.gov/pubmed/29673258
http://dx.doi.org/10.1177/1759091418766175
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