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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 human demyelinating diseases.

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Figure 1: Inactivation of peroxisome function in oligodendrocytes.
Figure 2: Abnormal lipid synthesis and metabolism.
Figure 3: Neurological impairments and premature death.
Figure 4: MRI.
Figure 5: Progressive demyelination and axonal loss in the subcortical white matter.
Figure 6: Reactive gliosis and neuroinflammation.

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Acknowledgements

We 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.

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Authors

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.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4 (PDF 731 kb)

Supplementary Video 1

Ataxia of Pex5flox/flox*Cnp1-Cre mice. Conditional Pex5 mutant mouse (Pex5flox/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)

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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

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