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

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.

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

“…In contrast, Singh's lab described cell death after ABCD1 loss, in rat B12 oligodendrocytic cells, but not in human U87 astrocytes, suggesting that oligodendrocytes are more sensitive to ABCD1 knockdown than astrocytes [155]. This higher sensitivity of oligodendrocytes to VLCFA but not the other neural cell types is consistent to the axonal loss and demyelination found out when functional peroxisomes are absent in 23 oligodendrocytes [156] but not in astrocytes nor neurons [157]. However, neither oligodendrocyte loss nor demyelination has been observed in X-ALD mouse models [18,40] indicating that ABCD1 deletion, alone, is not sufficient to kill oligodendrocytes in vivo in the mouse.…”

“…This implies that an excess of VLCFA levels in the myelin is not sufficient to exert a major direct impact on neurological functioning [157]. Similarly, mice with specific deletion of Pex5 in neurons (Nex-Pex5) exhibit no metabolic disturbance neither axonal damage [157]. Finally, Nestin-Pex5 mice, which harbor a deletion of Pex5 in the central and peripheral nervous system (of expression in oligodendrocytes, neurons, astrocytes and microglial cells), show an earlier onset phenotype than Cnp-Pex5 mice, which exhibit demyelination and axonal abnormalities associated with locomotor and cognitive deficits [158].…”

“…Absence of peroxisomes in astrocytes provokes defects in the myelin with increase of VLCFA content but no axonal loss nor demyelination. This implies that an excess of VLCFA levels in the myelin is not sufficient to exert a major direct impact on neurological functioning [157]. Similarly, mice with specific deletion of Pex5 in neurons (Nex-Pex5) exhibit no metabolic disturbance neither axonal damage [157].…”

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…CAT is a peroxisomal enzyme and is found in nearly all living organisms exposed to oxygen. Ablation of functional peroxisomes from all neural cells in mice causes remarkable neurological abnormalities including demyelination and axonal degeneration [100]. Its high turnover number (k cat ≈10 7 s −1 ) is an indirect indication that it plays a central role in the homeostasis of ROS.…”

Reductions in neuronal peroxisomes in multiple sclerosis grey matter

“…7 This raises the possibility that peroxisomal function is vital for the maintenance of myelin, the integrity of axons and protection of GM neuronal cell bodies within the CNS, particularly under conditions of inflammatory stress. 9 We hypothesise, therefore, that reduction in peroxisomal function may contribute to neuronal and axonal injury during the progressive phase of MS. In the present study, we sought to determine whether there are changes in peroxisomal gene and protein expression in MS GM.…”