Absence of Functional Peroxisomes from Mouse CNS Causes Dysmyelination and Axon Degeneration

Abstract

Peroxisomal metabolism is essential for normal brain development both in men and in mice. Using conditional knock-out mice, we recently showed that peroxisome deficiency in liver has a severe and persistent impact on the formation of cortex and cerebellum, whereas absence of functional peroxisomes from the CNS only causes developmental delays without obvious alteration of brain architecture.We now report that a substantial fraction of the latter Nes-Pex5 knock-out mice survive into adulthood but develop progressive motoric and coordination problems, impaired exploration, and a deficit in cognition and die before the age of 6 months. Histopathologically, both the white and gray matter of the CNS displayed a region-specific accumulation of neutral lipids, astrogliosis and microgliosis, upregulation of catalase, and scattered cell death. Nes-Pex5 knock-out mice featured a dramatic reduction of myelin staining in corpus callosum, whereas cerebellum and other white matter tracts were less affected or unchanged. This was accompanied by a depletion of alkenylphospholipids in myelin and differentially reduced immunoreactivity of myelin proteins. EM analysis revealed that myelin wrappings around axons did still form, but they showed a reduction in thickness relative to axon diameters. Remarkably, multifocal axonal damage occurred in the corpus callosum. Thereby, debris accumulated between axolemma and inner myelin surface and axons collapsed, although myelin sheaths remained present. These anomalies of myelinated axons were already present in juvenile mice but aggravated in adulthood. Together, loss of CNS peroxisomal metabolism both affects myelin sheaths and axonal integrity possibly via independent pathways.

The peroxisome: an update on mysteries

“…As complete peroxisomal knockout mouse models cannot discriminate if functional disturbances in a tissue are locally generated or are caused by toxic metabolites produced elsewhere, conditional knockouts for one organ or cell type have been generated during the last few years. The functional deletion of peroxisomes in brain-specific Pex5 knockout mice results in a severe neuronal phenotype comprising demyelination and degeneration of axons (Hulshagen et al 2008). Nevertheless, this model could not resolve whether the absence of functional peroxisomes in neurons themselves was the cause of these damages or if disturbances in glial cells exerted the detrimental effect on neurons.…”

Ectopic recombination in the central and peripheral nervous system by aP2/FABP4‐Cre mice: Implications for metabolism research

“…For immunofluorescent stainings, mice were perfused with 10% neutral buffered formalin and sectioned into 10 lm frozen sections as previously described [17]. The following primary antibodies were used: glial acidic fibrillary protein (GFAP) (Sigma, Bornem, Belgium) and neuronal nuclei (NeuN) (Chemicon, Temecula, USA) raised in mice at a 1/100 dilution; catalase (Rockland, Gilbertsville, PA) and b-galactosidase (Cappel, CA, USA) raised in rabbits at a 1/ 100 and 1/400 dilution.…”

Organelle dynamics and dysfunction: A closer link between peroxisomes and mitochondria

“…Furthermore, peroxisomal metabolism is essential for normal brain development. Studies on Pex5 knockout mice have revealed that peroxisomes provide oligodendrocytes with an essential neuroprotective function against axon degeneration, dysmyelination and neuroinflammation, which is relevant for human demyelinating diseases (Hulshagen et al 2008;Kassmann et al 2007).…”