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Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease II

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE269183 | GEO | 2024/07/04

REPOSITORIES: GEO

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Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease

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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Expression of expanded GGC repeats within NOTCH2NLC causes cardiac dysfunction in mouse models

Project description:Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system as well as multiple visceral organs. In 2019, expanded GGC repeats within the 5’ untranslated region of the NOTCH2NLC gene was identified as the causative factor. Although NIID primarily affects the central and peripheral nervous systems, growing evidence suggests potential cardiac abnormalities in NIID. However, the link between expanded GGC repeats within NOTCH2NLC and cardiac dysfunction remains uncertain. Results: In this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 ubiquitously or specifically in cardiomyocytes, and identified p62-positive intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes in two mouse models. We observed that both models exhibited cardiac-related pathological and echocardiographic changes, albeit exhibiting varying degrees of severity. Transcriptomic analysis revealed shared downregulation of genes related to ion channels and mitochondria in both models, with the cardiomyocyte-specific mice showing a more pronounced downregulation of mitochondria and energy metabolism-related pathways. Further investigations revealed decreased expression of mitochondria-related genes and electron transport chain activity. At last, we conducted a retrospective review of cardiac-related examination results from NIID patients at our hospital and also identified some cardiac abnormalities in NIID patients. Conclusions: Our study provided the first in vivo evidence linking GGC repeat expansions within NOTCH2NLC to cardiac abnormalities and highlighted the contribution of mitochondrial dysfunction in the development of cardiac abnormalities.

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GGC repeat expansion within NOTCH2NLC causes behavioral deficits and neurodegeneration through misregulated alternative splicing

Project description:GGC repeat expansion within NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here we have established both a transgenic mouse model and a human neural progenitor cell (hNPC) model. We show that the expression of the NOTCH2NLC gene with expanded GGC repeats produces multiple forms of polypeptides, including polyglycine (polyG), polyalanine (polyA) and polyarginine (polyR), and leads to widespread intranuclear inclusions, severe neurodegeneration, motor dysfunction and cognitive deficits, which faithfully mimics the clinical manifestations and pathological features associated with NIID. We further performed RNA-seq on the prefrontal cortex, cerebellum and hippocampus of the transgenic mice and on the hNPC model and identified a large proportion of conserved alternative splicing between the NIID mouse and hNPC cell models. Analyses of the conserved alternative splicing revealed the enrichment of the binding motif of hnRNPM. We found that hnRNPM could interact with and be sequestered by expanded NOTCH2NLC-polyG and -polyA. Functional expression of hnRNPM could ameliorate the cellular toxicity caused by expanded GGC repeats within NOTCH2NLC. These results together suggest that dysregulated alternative splicing could play a vital role in the molecular pathogenesis of NIID.

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C9orf72 deficiency promotes microglial mediated synaptic loss in aging and amyloid accumulation [bulk RNA-seq]

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GGC repeat expansion within NOTCH2NLC causes behavioral deficits and neurodegeneration through misregulated alternative splicing

Project description:GGC repeat expansion within NOTCH2NLC causes behavioral deficits and neurodegeneration through misregulated alternative splicing

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Neurodegeneration and Neuroinflammation are Linked, but Independent of α-Synuclein Inclusions, in a Seeding/Spreading Mouse Model of Parkinson’s Disease

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