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Cited by 78Metabolism and Genetic DisordersHereditary Neurological DisordersNeurological diseases and metabolism

Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes

Bottelbergs, Astrid, Verheijden, Simon, Hulshagen, Leen, Gutmann, David H., Goebbels, Sandra, Nave, Klaus‐Armin, Kassmann, Celia, Baes, Myriam·2010·Glia
DOI 10.1002/glia.21027
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Abstract

Ablation of functional peroxisomes from all neural cells in Nestin-Pex5 knockout mice caused remarkable neurological abnormalities including motoric and cognitive malfunctioning accompanied by demyelination, axonal degeneration, and gliosis. An oligodendrocyte selective Cnp-Pex5 knockout mouse model shows a similar pathology, but with later onset and slower progression. Until now, the link between these neurological anomalies and the known metabolic alterations, namely the accumulation of very long-chain fatty acids (VLCFA) and reduction of plasmalogens, has not been established. We now focused on the role of peroxisomes in neurons and astrocytes. A neuron-specific peroxisome knockout model, NEX-Pex5, showed neither microscopic nor metabolic abnormalities indicating that the lack of functional peroxisomes within neurons does not cause axonal damage. Axonal integrity and normal behavior was also preserved when peroxisomes were deleted from astrocytes in GFAP-Pex5(-/-) mice. Nevertheless, peroxisomal metabolites were dysregulated in brain including a marked accumulation of VLCFA and a slight reduction in plasmalogens. Interestingly, despite minor targeting of oligodendrocytes in GFAP-Pex5(-/-) mice, these metabolic perturbations were also present in isolated myelin indicating that peroxisomal metabolites are shuttled between different brain cell types. We conclude that absence of peroxisomal metabolism in neurons and astrocytes does not provoke the neurodegenerative phenotype observed after deleting peroxisomes from oligodendrocytes. Lack of peroxisomal metabolism in astrocytes causes increased VLCFA levels in myelin, but this has no major impact on neurological functioning.

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Crossref · 10.1002/glia.21027

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  • A NEX promoter-driven Pex5 KO showed that the lack of peroxisomes in neurons did not lead to VLCFA accumulation or brain dysfunction.

    “Another neuronal helix–loop–helix protein (NEX) promoter-driven Pex5 KO showed that the lack of peroxisomes in neurons did not lead to VLCFA accumulation or brain dysfunction, while another glial fibrillary acidic protein (GFAP) promoter-driven Pex5 KO showed that the lack of peroxisomes in astrocytes, despite causing VLCFA accumulation, had no significant impact on CNS functioning [264,266].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [264]

  • A GFAP promoter-driven Pex5 KO showed that the lack of peroxisomes in astrocytes, despite causing VLCFA accumulation, had no significant impact on CNS functioning.

    “Another neuronal helix–loop–helix protein (NEX) promoter-driven Pex5 KO showed that the lack of peroxisomes in neurons did not lead to VLCFA accumulation or brain dysfunction, while another glial fibrillary acidic protein (GFAP) promoter-driven Pex5 KO showed that the lack of peroxisomes in astrocytes, despite causing VLCFA accumulation, had no significant impact on CNS functioning [264,266].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [264]

  • Because neurons have few peroxisomes, they do not play a major role in VLCFA degradation.

    “Because neurons have few peroxisomes, they do not play a major role in VLCFA degradation, as demonstrated by NEX-Pex5 mice that have no peroxisomes in their neurons and no VLCFA accumulation [264].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [264]

  • 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 [264]

  • Peroxisome ablation in projection neurons of neocortex and hippocampus (Nex-Cre) or in astrocytes (GFAP-Cre) has no obvious deleterious effect on brain development or function.

    “In contrast, peroxisome ablation in projection neurons of neocortex and hippocampus, obtained with Nex-Cre driver mice [76], or in astrocytes obtained with GFAP-Cre drivers [76], had no obvious deleterious effect on brain development or function.”

    From Peroxisomes in brain development and function (2016) · cites this paper as [76]

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Authors
Bottelbergs, A., Verheijden, S., Hulshagen, L., Gutmann, D. H., Goebbels, S., Nave, K., Kassmann, C., & Baes, M.
Affiliations
  • KU Leuven (BE)
  • Washington University in St. Louis (US)
  • Max Planck Society (DE)
Corresponding author
Baes, Myriam
ORCID
Venue
Glia
Publisher
Wiley
Published
2010-08-03
Volume
58
Issue
13
Pages
1532-1543
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.21027
OpenAlex
W2112423730
Cited by
78
References
42
Citations by year
2026: 4 · 2025: 5 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 8 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 12 · 2012: 8
FWCI
5.04
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Glia (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek Vlaanderen (G.0760.09)
  • Geconcerteerde Onderzoeksacties (2004/08, OT (08/40)
  • European Union (LSHG-CT-2004-512018, FP6)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
peroxisomes, PEX5, axonal integrity, astrocytes, neurons, oligodendrocytes, very long chain fatty acids, plasmalogens, peroxisomal metabolism, demyelination, axonal degeneration, gliosis, myelin, neurodegeneration
MeSH terms
Peroxisome-Targeting Signal 1 Receptor, Animals, Animals, Newborn, Astrocytes, Axons, Behavior, Animal, Cells, Cultured, Cerebellum, Embryo, Mammalian, Myelin Basic Protein, Glial Fibrillary Acidic Protein, Intermediate Filament Proteins, Mice, Transgenic, Motor Activity, Myelin Sheath, Nerve Tissue Proteins, Neurons, Up-Regulation, Receptors, Cytoplasmic and Nuclear, Peroxisomes, Rotarod Performance Test, Lipid Metabolism, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Nestin

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