Kleinecke, S. et al. (2017) Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy. eLife, 6, e23332. (doi: 10.7554/elife.23332) (PMID:28470148) (PMCID:PMC5417850)
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Abstract
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.
Item Type: | Articles |
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Keywords: | Short report, neuroscience, peripheral neuropathy, peroxisomes, lysosomes, metabolic disorders, axo-glia interaction, myelin, mouse. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | McGonigal, Dr Rhona and Willison, Professor Hugh |
Creator Roles: | McGonigal, R.Formal analysis, Investigation, Methodology, Validation Willison, H.Formal analysis, Methodology |
Authors: | Kleinecke, S., Richert, S., de Hoz, L., Brügger, B., Kungl, T., Asadollahi, E., Quintes, S., Blanz, J., McGonigal, R., Naseri, K., Sereda, M. W., Sachsenheimer, T., Lüchtenborg, C., Möbius, W., Willison, H., Baes, M., Nave, K.-A., and Kassmann, C. M. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | eLife |
Publisher: | eLife Sciences Publications |
ISSN: | 2050-084X |
ISSN (Online): | 2050-084X |
Copyright Holders: | Copyright © 2017 Kleinecke et al. |
First Published: | First published in eLife 6:e23332 |
Publisher Policy: | Reproduced under a Creative Commons License |
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