Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes.
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.
Bottelbergs
Astrid
A
Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K. U. Leuven, B-3000 Leuven, Belgium.
Verheijden
Simon
S
Hulshagen
Leen
L
Gutmann
David H
DH
Goebbels
Sandra
S
Nave
Klaus-Armin
KA
Kassmann
Celia
C
Baes
Myriam
M
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology*; D001369:Axons / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004622:Embryo, Mammalian; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000166:cytology*; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency; D045442:Rotarod Performance Test / Q000379:methods; D015854:Up-Regulation / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D064231:Nestin; D000074435:Peroxisome-Targeting Signal 1 Receptor; D018160:Receptors, Cytoplasmic and Nuclear; C577485:Nes protein, mouse; C110701:Neurod6 protein, mouse; C000614265:Pex5 protein, mouse