Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

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
Keywords:Short report, neuroscience, peripheral neuropathy, peroxisomes, lysosomes, metabolic disorders, axo-glia interaction, myelin, mouse.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Willison, Professor Hugh and McGonigal, Dr Rhona
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 > Institute of Infection Immunity and Inflammation
Journal Name:eLife
Publisher:eLife Sciences Publications, Ltd
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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