Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system

Mice with peroxisome deficiency in neural cells (Nestin-Pex5 ^−/− ) develop a neurodegenerative phenotype leading to motor and cognitive disabilities and early death. Major pathologies at the end stage of disease include severe demyelination, axonal degeneration and neuroinflammation. We now investigated the onset and progression of these pathological processes, and their potential interrelationship. In addition, the putative role of oxidative stress, the impact of plasmalogen depletion on the neurodegenerative phenotype, and the consequences of peroxisome elimination in the postnatal period were studied.

Immunohistochemistry in association with gene expression analysis was performed on Nestin-Pex5 ^−/− mice to document demyelination, axonal damage and neuroinflammation. Also Gnpat ^−/− mice, with selective plasmalogen deficiency and CMV-Tx-Pex5 ^−/− mice, with tamoxifen induced generalized loss of peroxisomes were analysed.

Activation of the innate immune system is a very early event in the pathological process in Nestin-Pex5 ^−/− mice which evolves in chronic neuroinflammation. The complement factor C1q, one of the earliest up regulated transcripts, was expressed on neurons and oligodendrocytes but not on microglia. Transcripts of other pro- and anti-inflammatory genes and markers of phagocytotic activity were already significantly induced before detecting pathologies with immunofluorescent staining. Demyelination, macrophage activity and axonal loss co-occurred throughout the brain. As in patients with mild peroxisome biogenesis disorders who develop regressive changes, demyelination in cerebellum and brain stem preceded major myelin loss in corpus callosum of both Nestin-Pex5 ^−/− and CMV-Tx-Pex5 ^−/− mice. These lesions were not accompanied by generalized oxidative stress throughout the brain. Although Gnpat ^−/− mice displayed dysmyelination and Purkinje cell axon damage in cerebellum, confirming previous observations, no signs of inflammation or demyelination aggravating with age were observed.

Peroxisome inactivity triggers a fast neuroinflammatory reaction, which is not solely due to the depletion of plasmalogens. In association with myelin abnormalities this causes axon damage and loss.