Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy
Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann...
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eLife Sciences Publications Ltd
2017-05-01
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Online Access: | https://elifesciences.org/articles/23332 |
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author | Sandra Kleinecke Sarah Richert Livia de Hoz Britta Brügger Theresa Kungl Ebrahim Asadollahi Susanne Quintes Judith Blanz Rhona McGonigal Kobra Naseri Michael W Sereda Timo Sachsenheimer Christian Lüchtenborg Wiebke Möbius Hugh Willison Myriam Baes Klaus-Armin Nave Celia Michèle Kassmann |
author_facet | Sandra Kleinecke Sarah Richert Livia de Hoz Britta Brügger Theresa Kungl Ebrahim Asadollahi Susanne Quintes Judith Blanz Rhona McGonigal Kobra Naseri Michael W Sereda Timo Sachsenheimer Christian Lüchtenborg Wiebke Möbius Hugh Willison Myriam Baes Klaus-Armin Nave Celia Michèle Kassmann |
author_sort | Sandra Kleinecke |
collection | DOAJ |
description | Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels. |
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institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-11T10:33:25Z |
publishDate | 2017-05-01 |
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spelling | doaj.art-278b7784adc34b6b9b3600532a3126a22022-12-22T04:29:21ZengeLife Sciences Publications LtdeLife2050-084X2017-05-01610.7554/eLife.23332Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathySandra Kleinecke0Sarah Richert1Livia de Hoz2Britta Brügger3Theresa Kungl4Ebrahim Asadollahi5Susanne Quintes6Judith Blanz7Rhona McGonigal8Kobra Naseri9Michael W Sereda10Timo Sachsenheimer11Christian Lüchtenborg12Wiebke Möbius13https://orcid.org/0000-0002-2902-7165Hugh Willison14Myriam Baes15Klaus-Armin Nave16https://orcid.org/0000-0001-8724-9666Celia Michèle Kassmann17https://orcid.org/0000-0003-0993-9455Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyUniversity of Heidelberg, Biochemistry Center (BZH), Heidelberg, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyUnit of Molecular Cell Biology and Transgenic, Institute of Biochemistry, University of Kiel, Kiel, GermanyInstitute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United KingdomBirjand University of Medical Sciences, Birjand, IranDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyUniversity of Heidelberg, Biochemistry Center (BZH), Heidelberg, GermanyUniversity of Heidelberg, Biochemistry Center (BZH), Heidelberg, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyInstitute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, United KingdomDepartment of Pharmaceutical and Pharmacological Sciences, Cell Metabolism, KU Leuven- University of Leuven, Leuven, BelgiumDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyImpairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels.https://elifesciences.org/articles/23332peripheral neuropathyperoxisomeslysosomesmetabolic disordersaxo-glia interactionmyelin |
spellingShingle | Sandra Kleinecke Sarah Richert Livia de Hoz Britta Brügger Theresa Kungl Ebrahim Asadollahi Susanne Quintes Judith Blanz Rhona McGonigal Kobra Naseri Michael W Sereda Timo Sachsenheimer Christian Lüchtenborg Wiebke Möbius Hugh Willison Myriam Baes Klaus-Armin Nave Celia Michèle Kassmann Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy eLife peripheral neuropathy peroxisomes lysosomes metabolic disorders axo-glia interaction myelin |
title | Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy |
title_full | Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy |
title_fullStr | Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy |
title_full_unstemmed | Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy |
title_short | Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy |
title_sort | peroxisomal dysfunctions cause lysosomal storage and axonal kv1 channel redistribution in peripheral neuropathy |
topic | peripheral neuropathy peroxisomes lysosomes metabolic disorders axo-glia interaction myelin |
url | https://elifesciences.org/articles/23332 |
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