Pathogenicinflammation in the CNS of mice carrying humanPLP1mutations

Abstract

Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated the disease progression in mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of multiple sclerosis. These mouse models show loss-of-function of PLP1 associated with neuroinflammation; the latter leading to clinically relevant axonal degeneration, neuronal loss and brain atrophy as demonstrated by inactivation of the recombination activating gene 1. Moreover, these pathological hallmarks were substantially amplified when we attenuated immune regulation by inactivation of the programmed cell death-1 gene. Our observations support the view that primary oligodendroglial abnormalities can evoke pathogenically relevant neuroinflammation that drives neurodegeneration, as observed in some forms of multiple sclerosis but also in other, genetically-mediated neurodegenerative disorders of the human nervous system. As many potent immunomodulatory drugs have emerged during the last years, it is tempting to consider immunomodulation as a treatment option not only for multiple sclerosis, but also for so far non-treatable, genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.

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

“…Axonal damage and microglial activation are frequently but not always associated with an increased density of T‐lymphocytes (Ransohoff & Brown, ; Waisman, Liblau, & Becher, ). Indeed, T‐lymphocytes have been observed in brain tissue of the Plp transgenic‐overexpressor mouse model of PMD (Ip et al, ), the Plp null/Y mouse model of SPG2 (de Monasterio‐Schrader et al, ) and the Plp L30R and Plp R137W transgenic mouse models of PMD caused by missense mutations (Groh et al, ). We thus immunolabeled T‐lymphocytes using antibodies directed against CD3 and quantified the density of CD3 + cells in the fimbria at the age of 26 weeks (Figure a–f).…”

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

“…For instance, HSPs, such as SPG11 or SPG2, display commonalities with multiple sclerosis (MS) (Laurencin et al, 2016;Romagnolo et al, 2014;Rubegni et al, 2017). As already mentioned earlier, when transferred into the murine system, these human mutations not only present as loss-offunction mutations for PLP1 but also caused the typical "leukodystrophy-like" detrimental neuroinflammatory phenotype, with CD81 cytotoxic T-lymphocytes spatially targeting juxtaparanodes (Groh et al, 2016a). As already mentioned earlier, when transferred into the murine system, these human mutations not only present as loss-offunction mutations for PLP1 but also caused the typical "leukodystrophy-like" detrimental neuroinflammatory phenotype, with CD81 cytotoxic T-lymphocytes spatially targeting juxtaparanodes (Groh et al, 2016a).…”

“…Moreover, a recent study in distinct mouse mutants carrying human PLP1 loss-of-function mutations revealed a close association of CD81 T-lymphocytes and Sn1 microglial cells (see below) with juxtaparanodes of abnormal appearance containing altered organelles/mitochondria (Groh et al, 2016a). Again, both abnormal juxtaparanodal morphology and reduced axonal transport were strongly dependent on inflammatory reactions by the adaptive immune system (Groh et al, 2016a). Thus, CD81 cytotoxic T-cells have been identified as pivotal mediator of disease in a Plp1 overexpressing mouse mutant as well as in two mutants carrying distinct PLP1 loss-of-function mutations.…”

“…That inflammationpromoted neuron loss can also occur after primary glial perturbation is demonstrated by the Plp1-deficient or PLP1-mutant HSP models with disease relevance to progressive MS (Groh et al, 2016a). It is possible that the eventual neuronal cell death in the CLN models is partially driven by the expression of the mutant protein in neurons as opposed to the Plp1-overexpressing models where primary cellular perturbation is confined to myelinating glia.…”

“…Thus, inflammation might be a prominent modifier of this disease but it is not known why in some cases inflammation is prominent, but not in others. Crossbreeding of these models with mutants showing an attenuated limitation of inflammation due to PD-1-deficiency might be an option to increase the inflammatory impact (Groh et al, 2016a;Kroner et al, 2009b), potentially pushing the model into the direction of a more severe early-onset cerebral inflammatory demyelination. In the corresponding animal models, generated in different laboratories, the inflammatory component appears to be nearly absent (Berger et al, 2014;Moser, 2004), an unfortunate prerequisite for studying the respective, immune-related pathomechanisms.…”