Cytotoxic CNS-associated T cells drive axon degeneration in aging and myelin disease
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PROVIDER: PRJNA577691 | ENA |
REPOSITORIES: ENA
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Project description:1. Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon–myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages—important representatives of the innate immune system—are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses. Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function. 2. Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant oligodendrocyte myelin. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
2021-02-08 | GSE138891 | GEO
Project description:Axon degeneration and neurological dysfunction in myelin diseases is often attributed to loss of myelin. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. We have previously shown in mice that distinct defects in the proteolipid protein 1 gene result in axonal damage which is largely driven by cytotoxic T cells targeting myelinating oligodendrocytes. Here we show in these mutants that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce aberrant cytoskeletal plasticity within myelinating glial processes and constriction of axons at paranodal domains. Our study identifies detrimental axon-glia interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
2023-09-29 | GSE224032 | GEO
Project description:Genetically perturbed myelin as a risk factor for neuroinflammation-driven axon degeneration
| PRJNA929453 | ENA
Project description:To assess whether the CNS myelin proteome varies within the same species, we used quantitative mass spectrometry to compare myelin purified from mouse brains at three developmental timepoints (P18, P75, 6 months), brains of male and female mice, and four CNS regions (cortex, corpus callosum, optic nerve, spinal cord). We utilized a data-independent acquisition (DIA) workflow with alternating low and elevated energy (MSE) and an ion mobility-enhanced version thereof (referred to as UDMSE) to achieve both, a correct quantification of exceptionally abundant myelin proteins and a comprehensive coverage of the myelin proteome. Label-free protein quantification revealed that the myelin protein composition matures between P18 and P75, and remains largely similar up to 6 months. Proteins with decreasing abundance included cytoskeleton-associated proteins (regulating sheath growth and wrapping), whereas proteins with increasing abundance included all subunits of the septin filament (stabilizing mature myelin), and potentially protective proteins. Among the latter was quinoid dihydropteridine reductase (QDPR), which emerges as a highly specific marker for mature oligodendrocytes and myelin. Conversely, female and male mice display essentially similar myelin proteomes and the myelin-enriched fractions from the four CNS regions mainly differ by the abundance of HCN2-channels in spinal cord myelin as a requirement for particularly long sheaths, apart from the extent of contaminating mitochondrial and synaptic proteins.
2024-08-27 | PXD053062 | Pride
Project description:Rac1, a member of the small G protein Rho family, has been implicated in neurodegenerative diseases. However, its role in axon degeneration is not fully understood. Here we found that activation of Rac1 exacerbated axonal transport damage in an experimental glaucoma model. Inhibiting Rac1 activity by genetic or pharmacological methods alleviated the dysfunction of axonal transport and improved the integrity of microtubule by upregulating the expression of β-III tubulin and myelin basic protein. Rac1 interacted with Sirt1, a key molecule of Wallerian degeneration, which regulated the activity of PAK1, a downstream molecule of Rac1. Furthermore, Rac1 modulated Kif motors at the transcriptional level, among which Kif2a, a lysosome-location regulator, was negatively regulated by Rac1. Intravitreal injection of Kif2a siRNA reversed the improvement of Rac1 inhibition-mediated axonal transport through reducing autophagolysosomes. Our results suggest that Rac1/Kif2a accelerates the process of RGC axon degeneration by impairing the autophagic flux in glaucoma, which may be an intriguing therapy target for glaucoma.
2024-12-01 | GSE247696 | GEO
Project description:The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named Myelin-gene Regulatory Factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, pre-myelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities, and die due to seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination. We used microarrays to compare cultured oligodendrocytes (differentiated in vitro for 4 days) from MRF conditional knockouts and control litteramates to look at the effects of MRF deficiency on myelin gene expression. Mouse OPCs grown in vitro in the presence of PDGF serve as a baseline for gene expression prior to differentiation.
2009-05-31 | GSE15303 | GEO
Project description:We revisited the proteome of myelin biochemically purified from the brains of healthy c56Bl/6N-mice utilizing complementary proteomic approaches for deep qualitative and quantitative coverage. A data-independent acquisition (DIA) workflow with alternating low and elevated energy (MSE) provided the high dynamic range required for correct quantification of highest-abundance proteins. According to this analysis, the most abundant myelin proteins PLP, MBP, CNP and MOG constitute 38%, 30%, 5% and 1% of the total myelin protein, respectively. Combined with data from an ion mobility-enhanced version of the MSE mode (referred to as UDMSE) and from 1D-gel-based proteomic approaches, we provide the most comprehensive proteome resource of CNS myelin so far and correlate it with published datasets on mRNA and protein abundance profiles of myelin and oligodendrocytes. Using dynamic range enhancement (DRE)-UDMSE as a dedicated data acquisition mode for routine differential myelin proteome profiling, we also establish that the myelin proteome displays only minor changes if assessed after a post mortem-delay of six hours. Together, these data provide a basis for addressing proteomic heterogeneity of myelin in mouse models and human patients with white matter disorders.
2020-07-16 | PXD020007 | Pride
Project description:Axon degeneration sculpts precise patterns of connectivity in the developing nervous system and is an early pathological hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms that drive axon fragmentation, but far less is known about the upstream signaling pathways that initiate this process. Here we describe a role for the newly discovered axonal Membrane-associated Periodic Skeleton (MPS) –a quasi-1D periodic ultrastructure composed of actin, spectrin and associated molecules– during sensory axon degeneration. We find that trophic deprivation (TD) of sensory axons causes a rapid breakdown in the periodicity of the MPS in distal axons. These structural changes occur prior to and independently of caspase-driven axon fragmentation. We further show that acute actin destabilization to break down the MPS can initiate TD-related retrograde signaling. Actin stabilization prevents MPS breakdown during TD and blocks this signal. Moreover, deletion of βII-spectrin (Sptbn1), an obligate component of the MPS, suppresses this retrograde signaling and protects axons against degeneration. Together our data suggest that ultrastructural plasticity of the MPS underlies the earliest steps of axon degeneration.
2019-03-14 | PXD009854 | Pride
Project description:Purpose: Injuries to the adult central nervous system (CNS) often result in permanent disabilities because neurons lose the ability to regenerate their axon during development. Although the developmental transition from a growing to a transmitting phase may represent one of the first steps in the gradual loss of axon growth and regeneration ability, the molecular mechanisms regulating this process has yet to be identified. The main goal of this study was to dissect the molecular mechanisms mediating the decline in axon growth ability and its relationship with regeneration failure in the adult CNS. To this end, we sequenced the whole transcriptome of dorsal root ganglia (DRG) neurons in both growth competent and incompetent states at different developmental stages, in diverse culture and in vivo experimental conditions.
2016-09-17 | GSE66128 | GEO
Project description:Macrophages protect against sensory axon degeneration in diabetic neuropathy
| PRJNA1075431 | ENA