Time series of motor neuronal translatomes over the course of neuroinflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE220951 | GEO | 2023/11/06
REPOSITORIES: GEO
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Project description:During the course of multiple sclerosis (MS), inflammatory insults drive neuro-axonal loss and disability progression. However, pathways that guide neurons toward survival or death during central nervous system (CNS) inflammation are largely unexplored. Here we show that somatic deposition of the presynaptic protein bassoon (Bsn) in inflamed neurons directly contributes to neurodegeneration in MS. By comparing neuron-specific RNA-seq of healthy mice to mice undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identified key components of neurodegenerative pathways, including reduced mitochondrial ATP synthesis and increased protein catabolism. These changes were accompanied by neuronal induction and deposition of the intrinsically disordered protein Bsn in both EAE and in patients with MS. Somatic Bsn also accumulated in Bsn-overexpressing Neuro-2a (N2a) cells and single cell RNA-seq revealed dose-dependent repression of energy metabolism and induction of the unfolded protein response, reminiscent of our in vivo findings. Furthermore, Bsn overexpression in N2a cells or in Drosophila melanogaster neurons led to decreased survival and shortened lifespan, respectively. Conversely, genetic disruption of Bsn in mice was neuroprotective, with reduced neuro-axonal injury and clinical disability during EAE, establishing a toxic gain-of-function of Bsn during CNS inflammation. Our study provides systemic insights into neuronal responses to inflammation and identifies protein accumulation as a generic pathomechanism uniting primary and inflammatory neurodegeneration. Moreover, it offers a new explanation and possible treatment strategy to halt disability progression in MS, irrespective of immunotherapies.
2019-04-03 | GSE104898 | GEO
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2023-11-06 | GSE220950 | GEO
Project description:Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4 +CD44hiCD62L lo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide.
2016-09-12 | GSE85915 | GEO
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
2021-04-20 | GSE148931 | GEO
Project description:Objective: We previously reported that white matter connexin43 (Cx43) may related to the severity of the multiple sclerosis (MS), whereas the role of gray matter Cx43 in demyelinating disease is unknown. It was considered MS lesions were only exist in white matter, but recent studies revealed that demyelinating lesions are also exist in the cerebral cortex. This fact suggest the possibility that gray matter is somewhat related to the pathophysiology of MS. In this study, we aimed to clarify the role of gray matter Cx43 in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Methods: We developed Cx43F/F;Glutamate aspartate transporter (GLAST)-CreER(T2)KI/+ mice as gray matter specific Cx43 conditional knock-out (Cx43cKO) mice. We induced MOG-EAE 10 days after tamoxifen injection, and analyze its clinical course and pathology. We used Cx43F/F mice as controls. Results: EAE was significantly milder in gray matter astrocyte-specific Cx43cKO mice from acute phase to chronic phase, as compared with control mice. Pathology demonstrated less demyelinating lesions and infiltrating cells. Infiltrating immune cells did not express Cx43 in the active demyelinating lesions of the lumbar cord in both groups. The expression level of Cx43 was similar between these two groups in the spleen and the inguinal lymph nodes. Interpretation: Acute KO of gray matter specific Cx43 before induction of EAE reduce its aggressiveness. This finding may suggest the possibility that gray matter Cx43 modify the MS pathophysiology.
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Project description:Multiple Sclerosis (MS) is characterized by pathological inflammation resulting from recruitment of lymphoid and myeloid immune cells from the blood circulation into the central nervous system (CNS). Due to cellular heterogeneity, defining the functional roles of these subsets in acute and chronic stages of MS has been challenging. Here we used index sorting and transcriptional single-cell sequencing to characterize peripheral mononuclear phagocyte infiltrates in the MS mouse model, experimental autoimmune encephalomyelitis (EAE). Based on their transcriptomes, we identified eight monocyte and three dendritic cell subsets during disease pathology with defined characteristics pointing towards distinct functions. Cell ablation identified two specific monocytic subsets with a pathogenic potential. Congenic monocyte transfer experiments combined with indexed-lineage sorting coupled to scRNA-seq established that these pathogenic cells are not descendants of the canonical Ly6C+ monocytes but derived from early myeloid cell progenitors. These results suggest a potential for targeted therapeutic interventions aimed at blocking specific pathogenic monocytic subsets.
2020-04-20 | GSE144317 | GEO