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.DOI: http://dx.doi.org/10.7554/eLife.23332.001
Mutations of several genes encoding peroxisomal proteins have been associated with human diseases. Some of these display specific white matter abnormalities in the brain, although the affected proteins are ubiquitously expressed. To better understand the etiology of peroxisomal myelin diseases, we aimed to label these organelles in vivo and in a cell type specific fashion. We had previously shown that in oligodendrocytes and Schwann cells numerous peroxisomes reside in the cytoplasmic channels of "non-compacted" myelin. These organelles are smaller and biochemically distinct from non-myelin peroxisomes. Targeting peroxisomal functions in various cell types of the brain has demonstrated that oligodendroglial peroxisomes are specifically important for long-term integrity of the CNS. To visualize myelin peroxisomes in intact cells and tissues by live imaging, we have generated a novel line of transgenic mice for the expression of fluorescently tagged peroxisomes specifically in myelinating glia. This was achieved by modifying the gene for a photoconvertible mEos2 with a peroxisomal targeting signal type 1 (PTS1) and generating a fusion gene with the myelin-specific Cnp1 promoter. In the brain of resulting transgenic mice, peroxisomes are selectively labeled in oligodendrocytes. In this novel genetic tool, photoconversion of single peroxisomes from green to red fluorescence can be used to monitor the fate of single organelles and to determine the dynamics of PTS1-mediated protein import in the context of myelin diseases that affect peroxisomal functions.
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 K v 1-channels.
Many Thanks also to… …the whole PEX-lab group for the nice working atmosphere and all the scientific and nonscientific discussions. I especially thank Jenny Günther, the good soul of the group, for her comprehensive and patient help with technical issues. …the EM facility, Torben Ruhwedel, Dr. Wiebke Möbius and Boguslawa Sadowski for teaching and helping me a lot with the electron microscopy. …Dr. Judith Blanz and Meryem Senkara for their great help with lysosomal enzyme assays and providing antibodies. I'm especially grateful for welcoming and teaching me this technique. …Dr. Britta Brügger for her collaboration and doing lipid mass spectrometry. …Dr. Rhona McGonigal and Prof. Hugh Willison for providing antibodies and their great technical and theoretical support regarding gangliosides. …Dr. Livia de Hoz for advices and analysis of electrophysiological data. …Prof. Myriam Baes for her collaboration and providing mice. …Dr. Susanne Quintes, Dr. Theresa Kungl, and Dr. Julia Patzig for their advices and help concerning PNS biology. …Annette Fahrenholz, Ramona Jung, and Ulli Bode for technical help in many ways. …the animal caretakers for looking after my mice and thereby providing the basis of this work. …Michaela Schmalstieg and Gabriele Endo for organizational help. …Lothar Demel, Hans-Joachim Horn, Rolf Merker, and Harry Scherer for technical help concerning IT issues. …the whole Neurogenetics department for the great working atmosphere. I especially want to thank Sina, Jenny, Sarah, Dinah, Tim, and Jan for the great time in the lab and all the fun we had during the retreats. Abschließend geht ein großer Dank an meine Familie, die mich immer unterstützt hat und ohne die dies alles nicht möglich gewesen wäre. Ein besonderer Dank geht an Andreas Schmidt, der mir immer zu Seite stand und auch in schwierigen Phasen immer die richtigen Worte gefunden hat um mich zu motivieren. Content List of figures .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.