Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease II
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ABSTRACT:
PROVIDER: PRJNA1120470 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29299714_1.fastq.gz | Fastqsanger.gz | |||
| SRR29299714_2.fastq.gz | Fastqsanger.gz | |||
| SRR29299715_1.fastq.gz | Fastqsanger.gz | |||
| SRR29299715_2.fastq.gz | Fastqsanger.gz | |||
| SRR29299716_1.fastq.gz | Fastqsanger.gz |
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Project description:Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease
| PRJNA1119494 | ENA
Project description:Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by GGC repeat expansion of NOTCH2NLC. Despite the identification of uN2CpolyG, a toxic polyglycine (polyG) protein, the pathogenic mechanisms of NIID remain unclear. Herein, we investigated the role of polyG by expressing wild-type NOTCH2NLC, expanded NOTCH2NLC with 100 GGC repeats (translating or not translating into uN2CpolyG), or mutated NOTCH2NLC that encodes a pure polyG without GGC-repeat RNA and C-terminal stretch (uN2CpolyG-dCT) in mice. Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and caused neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathological lesions such as white matter lesions, microgliosis, and astrogliosis. By contrast, the sole expression of GGC-repeat RNA was non-pathogenic. Combining with bulk and single-nuclei RNA-seq, we determined the common molecular signatures associated with expressing uN2CpolyG and uN2CpolyG-dCT in the brain, especially the up-regulation of inflammation and microglia markers whereas down-regulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients by positron emission tomography, which correlated with white matter atrophy levels. Moreover, microglia ablation ameliorated neurodegeneration in uN2CpolyG-expressing mice but did not alter polyG inclusions. Together, these results demonstrate that polyG is critical for the pathogenesis of NIID, and microglia contribute to polyG-induced neurodegeneration.
2024-07-04 | GSE268950 | GEO
Project description:Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease caused by GGC repeat expansion of NOTCH2NLC. Despite the identification of uN2CpolyG, a toxic polyglycine (polyG) protein, the pathogenic mechanisms of NIID remain unclear. Herein, we investigated the role of polyG by expressing wild-type NOTCH2NLC, expanded NOTCH2NLC with 100 GGC repeats (translating or not translating into uN2CpolyG), or mutated NOTCH2NLC that encodes a pure polyG without GGC-repeat RNA and C-terminal stretch (uN2CpolyG-dCT) in mice. Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and caused neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathological lesions such as white matter lesions, microgliosis, and astrogliosis. By contrast, the sole expression of GGC-repeat RNA was non-pathogenic. Combining with bulk and single-nuclei RNA-seq, we determined the common molecular signatures associated with expressing uN2CpolyG and uN2CpolyG-dCT in the brain, especially the up-regulation of inflammation and microglia markers whereas down-regulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients by positron emission tomography, which correlated with white matter atrophy levels. Moreover, microglia ablation ameliorated neurodegeneration in uN2CpolyG-expressing mice but did not alter polyG inclusions. Together, these results demonstrate that polyG is critical for the pathogenesis of NIID, and microglia contribute to polyG-induced neurodegeneration.
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Project description:In this study, we used single-cell RNA-sequencing to gain unprecedented insight into the phenotypic heterogeneity and the transcriptional dynamics of microglia cells during the progression of neurodegeneration. Briefly, by using a severe neurodegeneration mouse model with Alzheimer’s-like pathology and phenotypes (CK-p25 model), we surveyed microglia activation by RNA sequencing longitudinally at fine temporal- and single-cell resolution. In summary, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered novel microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs. These insights into the molecular programs underlying microglia activation provided by our study may pave the way for designing new rational and efficient strategies to treat Alzheimer’s and other neurodegenerative diseases.
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2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
Project description:Purpose: RNASeq was used to identify transcriptional signature responsible for the metabolic reprogramming phenotype of microglia in neurodegenerative disease Result: We identified Ppargc1a/Cebpb signaling pathway as a critical axis that controls microglial glycolytic transition during neurodegeneration
2020-08-28 | GSE92550 | GEO
Project description:Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and increased risk of late-onset neurodegeneration. Surprisingly, we found microglia mutant clones associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the grey nuclei of the rhombencephalon, in patients with LCH and ECD whether or not they presented with clinical symptoms of neurodegeneration at the time of death. The presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1+ clones (p= 0.0003), indicating a phase of subclinical incipient neurodegeneration. Depletion of mutant microglia by a CSF1R-inhibitor in a mouse model of incipient disease limited neuronal loss and improved survival. Disease topography was attributable to a local proliferative advantage of mutant microglia. Genetic bar-coding analysis suggest that mutant clones originate from either definitive or yolk sac hematopoiesis depending on patients. These studies characterize a progressive neurodegenerative disease associated with clonal proliferation of inflammatory microglia (CPIM), and a preclinical stage of incipient disease which represents a therapeutic window for prevention of neuronal death.
2025-04-15 | GSE288761 | GEO
Project description:Microglia are brain immune cells that constantly survey their environment to maintain homeostasis. Enhanced microglial reactivity and proliferation are typical hallmarks of neurodegenerative diseases. Whether specific disease-linked microglial subsets exist during the entire course of neurodegeneration, including the recovery phase, is currently unclear. Taking a single-cell RNA-sequencing approach in a susceptibility gene-free model of nerve injury, we identified a microglial subpopulation that upon acute neurodegeneration shares a conserved gene regulatory profile compared to previously reported chronic and destructive neurodegeneration transgenic mouse models. Our data also revealed rapid shifts in gene regulation that defined microglial subsets at peak and resolution of neurodegeneration. Finally, our discovery of a unique transient microglial subpopulation at the onset of recovery may provide novel targets for modulating microglia-mediated restoration of brain health.
2018-08-25 | GSE90975 | GEO
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
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