Absence of functional peroxisomes from mouse central nervous system causes dysmyelination and axon degeneration
Afwezigheid van functionele peroxisomen in het het centrale zenuwstelstel van de muis veroorzaakt dysmyelinatie en axonale degeneratie
Hulshagen, Leen; M0224535
Loss or impairment of peroxisomal function, as seen in peroxisome biogenesis disorders, or mutations of individual peroxisomal enzymes or transporter proteins result in characteristic patterns of CNS lesions. Although in some cases the neuropathologies are associated with specific metabolic perturbations, no causal links have been experimentally proven and the pathomechanisms of the neurological abnormalities remain unresolved. The aim of this thesis was to better define the function of peroxisomesin postnatal CNS. To approach this question a mouse model was analyzed with selective elimination of functional peroxisomes from brain and spinal cord. The latter Nes-Pex5 knockout mice developed progressive motoric and coordination problems, impaired exploration and a deficit in cognition and died before the age of 24 weeks. Histopathologically, boththe white and grey matter of the CNS were characterized by the accumulation of neutral lipids, astro- and microgliosis, upregulation of catalase, mitochondrial abnormalities and scattered cell death. More specifically, Nes-Pex5 knockout mice featured severely reduced myelin stainability in corpus callosum and cerebellum, accompanied by a depletion of alkenyl-phospholipids and severely impaired immunohistochemical detection of the major myelin proteins MBP, PLP and CNP. Myelin wrappings aroundthe axons did still form, but were more variable both in thickness and degree of compaction. In addition, multifocal axonal damage was observedin corpus callosum and fornix which not always codistributed with the myelin defects. These abnormalities of myelinated axons were already present in juvenile mice and aggravated in adulthood.It was quite striking that the phenotypic appearance and course of lifeof Nes-Pex5 was very similar to that of MFP-2 knockout micewith impaired peroxisomal β-oxidation. Indeed, they both developedabnormal reflexes of the paws upon lifting, impaired coordination, progressive motoric inability, lethargy and death before the age of 24 weeks.Histopathologically, Nes-Pex5 and MFP-2 knockout mice shared lipid accumulations, astro- and microgliosis in the grey matter, mitochondrial abnormalities and increased expression of catalase. However, the developmental and sustained myelin abnormalities which were accompanied with massive microgliosis in the corpus callosum and cerebellar white matter were only seen in Nes-Pex5 and did not occur in MFP-2 knockout mice. Despite normal myelin, extensive axonal damage was already observed at an age of 3 weeks in brain of MFP-2 knockout mice. We can conclude that peroxisomes are indispensable organelles for the integrity of the CNS, for normal motoric activity and cognitive abilities. Loss of functional peroxisomes in the CNS critically affects composition and structure of myelin sheaths, but is also essential for axonal integrity, possibly via independent pathways. We propose that axonal damageand/or abnormalities in grey matter that are common between Nes-Pex5 and MFP-2 knockout mice, rather than dysmyelination, are responsible for the behavioural problems and early death of both mouse models. Further investigations are required to pinpoint the essential peroxisomal metabolic conversions and the cell types in which they occur in the CNS.