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Keywords:

peroxisome, Animals, Apoptosis, myelin, zellweger syndrome, Ataxia, plasmalogen, Axons, Behavior, Animal, fatty acid, Brain, knock-out mice, astrocyte, Catalase, axon, Central Nervous System, microglia, Central Nervous System Diseases, bifunctional protein-deficiency, Demyelinating Diseases, central-nervous-system, Dyskinesias, Exploratory Behavior, multifunctional protein-2, postnatal-development, Gliosis, Intermediate Filament Proteins, zellweger-syndrome, Lipid Metabolism, lipid extracts, fatty-acids, Mice, human brain, Mice, Knockout, Myelin Sheath, mice, expression, Nerve Degeneration, Nerve Tissue Proteins, Peroxisomes, Phenotype, Receptors, Cytoplasmic and Nuclear, Severity of Illness Index, Spinal Cord, Up-Regulation, Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Zellweger syndrome, BIFUNCTIONAL PROTEIN-DEFICIENCY, CENTRAL-NERVOUS-SYSTEM, MULTIFUNCTIONAL PROTEIN-2, POSTNATAL-DEVELOPMENT, ZELLWEGER-SYNDROME, LIPID EXTRACTS, FATTY-ACIDS, HUMAN BRAIN, MICE, EXPRESSION, Nestin, Peroxisome-Targeting Signal 1 Receptor, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery, 3209 Neurosciences

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.