Is involvement of inflammation underestimated in Pelizaeus–Merzbacher disease?

Marteyn, Antoine; Evercooren, Anne Baron-Van

doi:10.1002/jnr.23931

Cited by 9 publications

(5 citation statements)

References 54 publications

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“…While gliosis and infiltrating T‐cells were previously observed in the brains of Plp null/Y mice (de Monasterio‐Schrader et al, ; Lüders et al, ) and other PLP‐related disorders (Marteyn & Baron‐Van Evercooren, ), in the present model axonal spheroids and secondary neuropathology emerge within months when the Plp ‐gene is recombined in mature oligodendrocytes. Although it was impossible to temporally uncouple axonal spheroids from gliosis, our results indicate that axonal pathology precedes the infiltration of T‐cells.…”

Section: Discussionsupporting

confidence: 40%

Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Lüders

Nessler

Kusch

et al. 2019

Glia

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Proteolipid protein (PLP) is the most abundant integral membrane protein in central nervous system (CNS) myelin. Expression of the Plp‐gene in oligodendrocytes is not essential for the biosynthesis of myelin membranes but required to prevent axonal pathology. This raises the question whether the exceptionally high level of PLP in myelin is required later in life, or whether high‐level PLP expression becomes dispensable once myelin has been assembled. Both models require a better understanding of the turnover of PLP in myelin in vivo. Thus, we generated and characterized a novel line of tamoxifen‐inducible Plp‐mutant mice that allowed us to determine the rate of PLP turnover after developmental myelination has been completed, and to assess the possible impact of gradually decreasing amounts of PLP for myelin and axonal integrity. We found that 6 months after targeting the Plp‐gene the abundance of PLP in CNS myelin was about halved, probably reflecting that myelin is slowly turned over in the adult brain. Importantly, this reduction by 50% was sufficient to cause the entire spectrum of neuropathological changes previously associated with the developmental lack of PLP, including myelin outfoldings, lamellae splittings, and axonal spheroids. In comparison to axonopathy and gliosis, the infiltration of cytotoxic T‐cells was temporally delayed, suggesting a corresponding chronology also in the genetic disorders of PLP‐deficiency. High‐level abundance of PLP in myelin throughout adult life emerges as a requirement for the preservation of white matter integrity.

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Section: Discussionsupporting

confidence: 40%

Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Lüders

Nessler

Kusch

et al. 2019

Glia

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“…The intercellular cross‐talk in the diseased brain may include microglia‐dependent activation of astrocytes (Liddelow et al, ) as well as astrocyte‐dependent recruitment or activation of microglia (Jo et al, ; Skripuletz et al, ). Indeed, both microgliosis and astrogliosis occur in various SPG/PMD patients and mouse models (overview in Marteyn & Baron‐Van Evercooren, ) including the Plp null/Y mouse model of SPG2 (de Monasterio‐Schrader et al, ). We thus immunolabeled astrocytes using antibodies directed against GFAP and measured the relative area of immunopositivity (Figure a–f).…”

Section: Resultsmentioning

confidence: 99%

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

Lüders

Patzig

Simons

et al. 2017

Glia

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Proteolipid protein (PLP) is the most abundant integral membrane protein in compact central nervous system myelin, and null mutations of the PLP1 gene cause spastic paraplegia type 2 (SPG2). SPG2 patients and PLP-deficient mice exhibit only moderate abnormalities of myelin but progressive degeneration of long axons. Since Plp1 gene products are detected in a subset of neurons it has been suggested that the loss of neuronal Plp1 expression could be the cause of the axonal pathology. To test this hypothesis, we created mice with a floxed Plp1 allele for selective Cre-mediated recombination in neurons. We find that recombination of Plp1 in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial targeting of Plp1 is sufficient to cause the entire neurodegenerative spectrum of SPG2 including axonopathy and secondary neuroinflammation. We conclude that PLP-dependent loss of oligodendroglial support is the primary cause of axonal degeneration in SPG2.

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“…Microglial activation has also been reported in other leukodystrophies [16, 84,126] such as in X-linked adrenoleukodystrophy (X-ALD) where prelesional areas with intact myelin are demarcated by loss of microglial TMEM119 and P2RY12 expression. Additionally, in metachromatic leukodystrophy (MLD) patches of amoeboid microglia that downregulate TMEM119 and P2RY12 show evidence of myelin phagocytosis in the normal appearing white matter (NAWM) [16].…”

Section: Leukodystrophiesmentioning

confidence: 85%

White matter microglia heterogeneity in the CNS

et al. 2021

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Microglia, the resident myeloid cells in the central nervous system (CNS) play critical roles in shaping the brain during development, responding to invading pathogens, and clearing tissue debris or aberrant protein aggregations during ageing and neurodegeneration. The original concept that like macrophages, microglia are either damaging (pro-inflammatory) or regenerative (anti-inflammatory) has been updated to a kaleidoscope view of microglia phenotypes reflecting their wideranging roles in maintaining homeostasis in the CNS and, their contribution to CNS diseases, as well as aiding repair. The use of new technologies including single cell/nucleus RNA sequencing has led to the identification of many novel microglia states, allowing for a better understanding of their complexity and distinguishing regional variations in the CNS. This has also revealed differences between species and diseases, and between microglia and other myeloid cells in the CNS. However, most of the data on microglia heterogeneity have been generated on cells isolated from the cortex or whole brain, whereas white matter changes and differences between white and grey matter have been relatively understudied. Considering the importance of microglia in regulating white matter health, we provide a brief update on the current knowledge of microglia heterogeneity in the white matter, how microglia are important for the development of the CNS, and how microglial ageing affects CNS white matter homeostasis. We discuss how microglia are intricately linked to the classical white matter diseases such as multiple sclerosis and genetic white matter diseases, and their putative roles in neurodegenerative diseases in which white matter is also affected. Understanding the wide variety of microglial functions in the white matter may provide the basis for microglial targeted therapies for CNS diseases.

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Is involvement of inflammation underestimated in Pelizaeus–Merzbacher disease?

Cited by 9 publications

References 54 publications

Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Maintenance of high proteolipid protein level in adult central nervous system myelin is required to preserve the integrity of myelin and axons

Genetic dissection of oligodendroglial and neuronalPlp1function in a novel mouse model of spastic paraplegia type 2

White matter microglia heterogeneity in the CNS

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