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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- neuroimmunology --- central nervous system --- immune system --- CNS repair --- CNS disorders

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- neuroimmunology --- central nervous system --- immune system --- CNS repair --- CNS disorders --- neuroimmunology --- central nervous system --- immune system --- CNS repair --- CNS disorders

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• Reference Manager
• EndNote
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De belangrijkste afwijkingen in peroxisomale aandoeningen zijn van neurologische aard. Peroxisomale ziekten kunnen veroorzaakt worden door een biogenesedefect of door mutaties in genen die coderen voor peroxisomale enzymen of transportproteïnen. Nochtans blijven tot op heden de onderliggende pathogene mechanismen die verantwoordelijk zijn voor de neurologische afwijkingen onopgehelderd. Het doel van deze studie was de functie van peroxisomen in het postnataal centraal zenuwsysteem beter te achterhalen. Hiervoor werd een muismodel ontwikkeld waarbij functionele peroxisomen selectief geëlimineerd werden uit hersenen en ruggenmerg. Deze Nes-Pex5 knockout-muizen ontwikkelden motorische- en coördinatieproblemen, exploratie- en bewustzijnsdefecten en ze stierven voor een leeftijd van 24 maanden. Het centraal zenuwstelsel vertoonde ernstige defecten. In de witte en grijze stof werden lipidenopstapelingen, astro- en microgliose, opregulatie van catalase, mitochondriale veranderingen en sporadische celdood gedocumenteerd. Een vermindering van kleuring van myelinelipiden werd waargenomen in het corpus callosum en cerebellum in Nes-Pex5 knockout-muizen wat gepaard ging met afwezigheid van alkenyl-fosfolipiden en een sterk verminderde immunohistochemische detectie van belangrijke myeline proteïnen zoals MBP, PLP en CNP. Desalniettemin werd er op ultrastructureel niveau myeline rond zenuwuitlopers waargenomen maar de dikte en compressie van myeline was abnormaal in vergelijking met controle-muizen. Ook werd axonale schade gedocumenteerd hetgeen niet altijd met de myelinedefecten correleerde. Myelineveranderingen werden reeds waargenomen op een leeftijd van 3 weken en werden ernstiger met de leeftijd. Opvallend was het gelijkaardig fenotype en levensverloop van Nes-Pex5 met MFP-2 knockout- muizen die een peroxisomaal β-oxidatiedefect hebben. Beide muismodellen trokken de poten verkrampt samen als men ze optilde bij hun staart en ze vertoonden motorische afwijkingen. Coördinatiestoornissen werden waargenomen en ze stierven beiden voor de leeftijd van 24 weken. Ook op histologisch vlak waren er sterke gelijkenissen nl. lipidenopstapelingen, astro- en microgliose in de grijze stof, mitochondriale abnormaliteiten en verhoogde expressie van catalase. Myeline abnormaliteiten met overheersende microgliose in de witte stof werden echter niet waargenomen in de MFP-2 knockout-muizen. Ondanks het normaal myeline werd op een leeftijd van 3 weken toch axonale schade geobserveerd in de hersenen van de MFP-2 knockout-muizen. We kunnen concluderen dat peroxisomen onmisbare organellen zijn voor de integriteit van het centraal zenuwstelsel, voor normale motorische activiteit en het leergedrag. Afwezigheid van functionele peroxisomen in het centraal zenuwstelsel heeft een invloed op samenstelling en structuur van myeline maar is ook essentieel voor axonale integriteit, mogelijk via onafhankelijke wegen. Toch kunnen we suggereren dat de axonale schade en/of de afwijkingen in de grijze stof, die Nes-Pex5 en MFP-2 knockout-muizen gemeenschappelijk hebben, en niet de dysmyelinatie, verantwoordelijk zijn voor de gedragsproblemen en de vroege sterfte van beide muismodellen. Verder onderzoek is vereist om te achterhalen welke de rol is van peroxisomale omzettingen in de verschillende celtypes in het centraal zenuwstelsel. 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 peroxisomes in 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, both the 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 around the axons did still form, but were more variable both in thickness and degree of compaction. In addition, multifocal axonal damage was observed in 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 life of Nes-Pex5 was very similar to that of MFP-2 knockout mice with impaired peroxisomal β-oxidation. Indeed, they both developed abnormal 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 damage and/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. samen als men ze optilde bij hun staart en ze vertoonden motorische afwijkingen. Coördinatiestoornissen werden waargenomen en ze stierven beiden voor de leeftijd van 24 weken. Ook op histologisch vlak waren er sterke gelijkenissen nl. lipidenopstapelingen, astro- en microgliose in de grijze stof, mitochondriale abnormaliteiten en verhoogde expressie van catalase. Myeline abnormaliteiten met overheersende microgliose in de witte stof werden echter niet waargenomen in de MFP-2 knockout-muizen. Ondanks het normaal myeline werd op een leeftijd van 3 weken toch axonale schade geobserveerd in de hersenen van de MFP-2 knockout-muizen. We kunnen concluderen dat peroxisomen onmisbare organellen zijn voor de integriteit van het centraal zenuwstelsel, voor normale motorische activiteit en het leergedrag. Afwezigheid van functionele peroxisomen in het centraal zenuwstelsel heeft een invloed op samenstelling en structuur van myeline maar is ook essentieel voor axonale integriteit, mogelijk via onafhankelijke wegen. Toch kunnen we suggereren dat de axonale schade en/of de afwijkingen in de grijze stof, die Nes-Pex5 en MFP-2 knockout-muizen gemeenschappelijk hebben, en niet de dysmyelinatie, verantwoordelijk zijn voor de gedragsproblemen en de vroege sterfte van beide muismodellen. Verder onderzoek is vereist om te achterhalen welke de rol is van peroxisomale omzettingen in de verschillende celtypes in het centraal zenuwstelsel. V. Summary 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 peroxisomes in 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, both the 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 around the axons did still form, but were more variable both in thickness and degree of compaction. In addition, multifocal axonal damage was observed in 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 life of Nes-Pex5 was very similar to that of MFP-2 knockout mice with impaired peroxisomal β-oxidation. Indeed, they both developed abnormal 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 damage and/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.