Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes

ABSTRACT Oligodendrocytes myelinate axons for rapid impulse conduction and contribute to normal axonal functions in the central nervous system. In multiple sclerosis, demyelination is caused

by autoimmune attacks, but the role of oligodendroglial cells in disease progression and axon degeneration is unclear. Here we show that oligodendrocytes harbor peroxisomes whose function

is essential for maintaining white matter tracts throughout adult life. By selectively inactivating the import factor PEX5 in myelinating glia, we generated mutant mice that developed

normally, but within several months showed ataxia, tremor and premature death. Absence of functional peroxisomes from oligodendrocytes caused widespread axonal degeneration and progressive

subcortical demyelination, but did not interfere with glial survival. Moreover, it caused a strong proinflammatory milieu and, unexpectedly, the infiltration of B and activated CD8+ T cells

into brain lesions. We conclude that peroxisomes provide oligodendrocytes with an essential neuroprotective function against axon degeneration and neuroinflammation, which is relevant for

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS REMYELINATION PROTECTS NEURONS FROM DLK-MEDIATED NEURODEGENERATION Article Open access 23 October 2024

MICROGLIA-MEDIATED DEMYELINATION PROTECTS AGAINST CD8+ T CELL-DRIVEN AXON DEGENERATION IN MICE CARRYING PLP DEFECTS Article Open access 30 October 2023 DOR ACTIVATION IN MATURE

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dedicate this paper to Hugo Moser for his pioneering work on peroxisomes in childhood neurological diseases. We thank J. Barth, U. Bode, A. Fahrenholz, A. Nave, S. Relitz and S. Hühold for

excellent technical assistance, and gratefully acknowledge J. Gärtner and D.H. Hunneman for clinical diagnostic service (VLCFA). This work was funded by grants from the European Union (PEX

and X-ALD), the US National Multiple Sclerosis Society, the Hertie Foundation, and the generous support of the private Liley and Del Marmol Foundations. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, Göttingen, D-37075, Germany Celia M Kassmann, Corinna Lappe-Siefke, Hauke B

Werner & Klaus-Armin Nave * Laboratory for Cell Metabolism, Faculty of Pharmacy, Katholieke Universiteit Leuven, Leuven, 3000, Belgium Myriam Baes * Biochemie-Zentrum, Universität

Heidelberg, Heidelberg, D-69120, Germany Britta Brügger * Department of Neuropathology, University of Göttingen, Göttingen, D-37075, Germany Alexander Mildner & Marco Prinz *

Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut für biophysikalische Chemie, Göttingen, 37077, Germany Oliver Natt, Thomas Michaelis & Jens Frahm Authors * Celia M Kassmann

View author publications You can also search for this author inPubMed Google Scholar * Corinna Lappe-Siefke View author publications You can also search for this author inPubMed Google

Scholar * Myriam Baes View author publications You can also search for this author inPubMed Google Scholar * Britta Brügger View author publications You can also search for this author

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publications You can also search for this author inPubMed Google Scholar * Klaus-Armin Nave View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

C.M.K. performed the analyses and drafted the manuscript. C.L.-S. provided _Cnp-Cre_ and M.B. provided _Pex5_ floxed mice. B.B. determined myelin lipids by mass spectroscopy. A.M. and M.P.

performed FACS analysis and quantified cytokines. H.B.W. participated in mouse genetics. O.N., T.M. and J.F. performed MRI. K.-A.N. designed the study and finalized the manuscript.

CORRESPONDING AUTHOR Correspondence to Klaus-Armin Nave. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY

TEXT AND FIGURES Supplementary Figures 1–4 (PDF 731 kb) SUPPLEMENTARY VIDEO 1 Ataxia of _Pex5__flox/flox*__Cnp1-Cre_ mice. Conditional _Pex5_ mutant mouse (_Pex5__flox/flox*__Cnp1-Cre_)

with hind limb ataxia as found in clinical stage III-IV. Motor defects are obvious when the mouse is placed on a cage top (slow motion video). (MOV 1096 kb) RIGHTS AND PERMISSIONS Reprints

and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Kassmann, C., Lappe-Siefke, C., Baes, M. _et al._ Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. _Nat

Genet_ 39, 969–976 (2007). https://doi.org/10.1038/ng2070 Download citation * Received: 11 January 2007 * Accepted: 14 May 2007 * Published: 22 July 2007 * Issue Date: August 2007 * DOI:

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