A cellular taxonomy of the adult human spinal cord

Neuron, Journal Year: 2023, Volume and Issue: 111(3), P. 328 - 344.e7

Published: Feb. 1, 2023

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding cellular diversity, characterizing human biology directly is important to uncover specialized features basic function pathology. Here, we present taxonomy the adult using single-nucleus RNA sequencing with spatial transcriptomics antibody validation. We identified 29 glial clusters 35 neuronal clusters, organized principally by anatomical location. To demonstrate relevance this resource disease, analyzed motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) other diseases. found that compared neurons, motoneurons are defined genes related size, cytoskeletal structure, ALS, suggesting molecular repertoire underlying their selective vulnerability. include web facilitate further investigations into biology.

Language: Английский

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Defining the molecular identity and morphology of glia limitans superficialis astrocytes in vertebrates

Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115344 - 115344

Published: Feb. 20, 2025

Language: Английский

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Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron loss. Microglia and astrocyte-driven neuroinflammation prominent in ALS, but the cell state dynamics pathways driving remain unclear. We performed single-nucleus RNA sequencing of ALS spinal cords identified altered glial states, including increased expression inflammatory activation markers. Many these signals converged on inflammation death regulator receptor-interacting protein kinase 1 (RIPK1) necroptotic pathway. In superoxide dismutase (SOD1)G93A mice, blocking RIPK1 activity delayed symptom onset impairment modulated responses. used human induced pluripotent stem (iPSC)-derived neuron, astrocyte, microglia tri-cultures to identify potential biomarkers that are secreted upon vitro inhibition cerebrospinal fluid (CSF) people with ALS. These data reveal ALS-enriched populations associated suggest deleterious role for neuroinflammatory signaling pathogenesis.

Language: Английский

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Defining the molecular identity and morphology ofglia limitans superficialisastrocytes in mouse and human

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 6, 2023

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and are, at least part, associated with their anatomical location can be restricted to strategically important domains. Here, we report forming glia limitans superficialis, outermost border of brain spinal cord, specialized astrocyte identified by single marker: Myocilin (Myoc). We show Myoc+ cover entire cord surface, exhibit an atypical morphology, evolutionarily conserved from rodents humans. Identification this will advance our understanding CNS homeostasis potentially targeted for therapeutic intervention combat peripheral inflammatory effects on CNS.

Language: Английский

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Integrated transcriptomic profiling reveals a STING-mediated Type II Interferon signature in SOD1-mutant amyotrophic lateral sclerosis models

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: March 2, 2025

Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS), particularly in cases with SOD1 mutations. Using integrative transcriptomics, we analyzed gene expression changes mouse models throughout progression, human induced-pluripotent stem cells (hiPSCs), and post-mortem spinal cord tissue from ALS patients. We identified conserved upregulation interferon (IFN) genes IFN-stimulating (ISGs) both ALS, predominance Type I IFNs (IFN-α/β) mice II (IFN-γ) humans. In models, observed robust sustained ISGs, including ATF3, beginning at disease onset stage persisting progression. Single-cell transcriptomics further pinpointed vascular endothelial as major source ISGs. Furthermore, found that the STING-TBK1 axis essential for induction ISGs its deletion impaired their expression. Our study uncovers signature across patients, highlighting potential role innate immune activation pathogenesis. These findings suggest may serve biomarkers therapeutic targets ALS. Integrative patients reveals type driven by STING-mediated activation.

Language: Английский

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CREB3 gain of function variants protect against ALS

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 26, 2025

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics CSN using published snRNA-seq data motor cortex ALS control postmortem tissues, longitudinal RNA-seq on purified male Sod1G86R mice. We report that undergo ER stress altered mRNA translation, identify transcription factor CREB3 its regulatory network as resilience marker ALS, not only amongst vulnerable neuronal populations, but across all populations well other cell types. Using genetic epidemiologic analyses further rare variant CREB3R119G (rs11538707) positive modifier in ALS. Through gain function, decreases risk developing progression rate patients. Cross-species unravels markers Genetics epidemiology protective CREB3R119G.

Language: Английский

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Exploring Neuregulin3: From physiology to pathology, a novel target for rational drug design

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116964 - 116964

Published: May 1, 2025

Language: Английский

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Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(3), P. e0299567 - e0299567

Published: March 8, 2024

Amyotrophic lateral sclerosis (ALS) is neurodegenerative disease characterized by a progressive loss of motor neurons resulting in paralysis and muscle atrophy. One the most prospective hypothesis on ALS pathogenesis suggests that excessive inflammation advanced glycation end-products (AGEs) accumulation play crucial role development patients SOD1 G93A mice. Hence, we may speculate RAGE, receptor for its proinflammatory ligands such as: HMGB1, S100B CML contribute to pathogenesis. The aim our studies was decipher RAGE as well provide insight into signaling pathways during progression RAGE-deficient In study, observed alternations molecular pattern KO mice compared Moreover, amount beta actin (ACTB) Glial fibrillary acidic protein (GFAP) elevated when with deletion RAGE. These data contributes understanding implications highlight potential targeted therapeutic interventions at early stage this devastating disease. inhibition cross-talk between abolish neuroinflammation, gliosis neuron damage hypothesize attenuated interaction improve well-being health status Therefore, emphasize pathway be target diseases.

Language: Английский

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Genomic and transcriptomic advances in amyotrophic lateral sclerosis

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 92, P. 102126 - 102126

Published: Nov. 15, 2023

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical molecular heterogeneity. In vitro in vivo models coupled with multiomic techniques have provided important contributions to unraveling pathomechanisms underlying ALS. To date, despite promising results accumulating knowledge, an effective treatment still lacking. Here, we provide overview of literature on use genomics, epigenomics, transcriptomics microRNAs deeply investigate mechanisms developing sustaining We report relevant genes implicated pathogenesis, discussing different high-throughput sequencing role epigenomic modifications. Furthermore, present transcriptomic studies recent advances, from microarrays bulk single-cell RNA sequencing. Finally, discuss as potential biomarkers tools for intervention. The integration data multiple omic approaches may new insights into pathogenic pathways by shedding light diagnostic prognostic biomarkers, helping stratify patients clinically subgroups, revealing novel therapeutic targets supporting development therapies.

Language: Английский

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Cortical glia in SOD1(G93A) mice are subtly affected by ALS-like pathology

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: April 21, 2023

Abstract The role of glia in amyotrophic lateral sclerosis (ALS) is undeniable. Their disease-related activity has been extensively studied the spinal cord, but only partly brain. We present herein a comprehensive study cortex SOD1(G93A) mice—a widely used model ALS. Using single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, we inspected astrocytes, microglia, oligodendrocytes, four stages disease, respecting factor sex. report minimal changes throughout disease progression regardless Pseudobulk analyses revealed subtle transcriptional alterations at end-stage microglia which were supported by immunohistochemistry. Therefore, our data support hypothesis that mouse does not recapitulate patients, recommend use different for future studies cortical ALS pathology.

Language: Английский

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