Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes
Open accessAbstract
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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In the CNP-Pex5 mouse brain, VLCFA accumulation is prominent in oligodendrocytes, notable in astrocytes, and non-existent in neurons.
“In the 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP)-Pex5 mouse brain, VLCFA accumulation is prominent in OLs, notable in astrocytes, and non-existent in neurons [166].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
Brain OLs account for the majority of VLCFA synthesis by using their ELOVL1.
“Brain OLs account for the majority of VLCFA synthesis [166,204] by using their ELOVL1 [205,206,207,208].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
OL peroxisomes are largely responsible for VLCFA synthesis and degradation in the adult brain.
“OL peroxisomes are largely responsible for VLCFA synthesis [204] and degradation [166] in the adult brain.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
The CNP-Pex5 mutant mouse provided a striking phenocopy of human cALD, with disease onset following normal developmental myelination.
“This CNP-Pex5 mutant mouse provided a striking phenocopy of human cALD, with disease onset following normal developmental myelination.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
The brains of CNP-Pex5 mutant mice showed strong VLCFA accumulation in myelin, severe axonal loss, severely lower plasmalogen levels, and early microglial increase in white matter, followed by demyelination with characteristic regional variability and inflammation with infiltrating perivascular macrophages and B and T cells.
“The brains of these mice showed strong VLCFA accumulation in myelin, severe axonal loss, severely lower plasmalogen levels, and early microglial increase in white matter, followed by demyelination with characteristic regional variability and inflammation with infiltrating perivascular macrophages and B and T cells.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
Microglia have abundant peroxisome content and express abundant ALDP in normal microglia in human and mouse brains.
“Their peroxisome content is abundant [166,253,315], and they express abundant ALDP in normal microglia in human and mouse brains [156].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
Astrocytes in GFAP-Pex5 KO mice have strong VLCFA accumulation, albeit inferior to that seen in the oligodendrocytes of CNP-Pex5 KO mice.
“Astrocytes in GFAP-Pex5 KO mice have strong VLCFA accumulation, albeit inferior to that seen in the OLs of CNP-Pex5 KO mice [166,264].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
X-ALD pathogenesis seems to be governed by two major mechanisms acting primarily in oligodendrocytes: VLCFA accumulation, which causes AMN and is cALD permissive, and a secondary peroxisomal pathology, suggested to be a necessary added mechanism of cALD.
“X-ALD pathogenesis seems to be governed by two major mechanisms acting primarily in OLs: VLCFA accumulation, which causes AMN and is cALD permissive, and a secondary peroxisomal pathology, suggested to be a necessary added mechanism of cALD [166].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [166]
Selective knockout of Pex5 in oligodendrocytes using Cnp-Cre drivers has severe consequences for the adult brain.
“Similarly, selective knockout (KO) of Pex5 in oligodendrocytes by using Cnp-Cre drivers had severe consequences for the adult brain [75].”
From Peroxisomes in brain development and function (2016) · cites this paper as [75]
Mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells.
“This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94].”
From X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects (2012) · cites this paper as [94]
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- Authors
- Kassmann, C. M., Lappe-Siefke, C., Baes, M., Brügger, B., Mildner, A., Werner, H. B., Natt, O., Michaelis, T., Prinz, M., Frahm, J., & Nave, K.-A.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- Max Planck Society (DE)
- KU Leuven (BE)
- Heidelberg University (DE)
- University of Göttingen (DE)
- Corresponding author
- Nave, Klaus-Armin
- ORCID
- Venue
- Nature Genetics
- Published
- 2007-07-22
- Volume
- 39
- Issue
- 8
- Pages
- 969-976
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1971817019
- Cited by
- 357
- References
- 49
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 19 · 2023: 20 · 2022: 12 · 2021: 14 · 2020: 16 · 2019: 7 · 2018: 18 · 2017: 15 · 2016: 17 · 2015: 14 · 2014: 20 · 2013: 31 · 2012: 28
- FWCI
- 17.46
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- peroxisomes, oligodendrocytes, PEX5, axonal degeneration, demyelination, neuroinflammation, multiple sclerosis, white matter, myelination, neuroprotection, CD8+ T cells, B cells, demyelinating disease, mouse mutants
- MeSH terms
- Peroxisome-Targeting Signal 1 Receptor, Animals, Axons, Demyelinating Diseases, Humans, Nerve Fibers, Myelinated, Oligodendroglia, T-Lymphocyte Subsets, Receptors, Cytoplasmic and Nuclear, CD8-Positive T-Lymphocytes, Peroxisomes, Lipid Metabolism, Mice
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