Amyotrophic Lateral Sclerosis Transcriptomics Reveals Immunological Effects of Low-Dose Interleukin-2.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE163560 | GEO | 2021/06/30
REPOSITORIES: GEO
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Project description:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive paralysis resulting from specific degeneration of upper and lower motor neurons (MNs). Chronic neuroinflammation, mediated by activated microglia, is a hallmark of patients diagnosed with ALS, and correlates with disease pathogenesis. Protecting MNs, particularly from toxic insults caused by neuroinflammation, could lead to effective treatments of ALS patient. Here, we report a screening campaign identifying a series of pyrazolotriazines that cell-autonomously protect MNs against neuroinflammation. We demonstrate that these compounds inhibit Cyclin-dependent kinase 5 (CDK5) and Glycogen synthase kinase 3 (GSK3), and we use phospho-proteomics to show that neuroprotection is linked to alterations in microtubule dynamics.
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Project description:The rate of disease progression widely varies between patients with amyotrophic lateral sclerosis (ALS). Prognostic assessment using biomarkers is highly preferred for planning medical care and improving the design of clinical trials. Therefore, the current study aimed to assess prognostic biomarkers for predicting future functional decline in patients with ALS. The prospective progression rate was calculated using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) at CSF collection and in 6 months. The ALS patients were classified into slow, intermediate, and fast progression groups. We performed comprehensive proteomic analyses of the CSF samples. In total, 26 proteins changed significantly (p < 0.05 and q < 0.10), with levels varying within a large dynamic range (fold change of > 1.5 or < 0.5). A receiver operating characteristic curve analyses showed that the following proteins showed high discrimination power between slow and fast progression groups: GPNMB, GFAP, GPC1, MGAT2, and CHI3L2. Of these, GPNMB, GPC1, and CHI3L2 were significantly correlated to prognostic progression rate. This study demonstrated that CSF levels of neuroinflammation and glycosylation-related proteins were significantly correlated with prospective progression rates in patients with ALS. These proteins could be useful prognostic biomarkers for ALS.
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Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA binding protein TDP-43. TDP-43 regulatesRNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We used Bru-seq and BruChase-seq to assessgenome-wide RNA stabilityinALS patient-derived cells,demonstratingprofound destabilization of ribosomal and mitochondrial transcripts. This pattern wasrecapitulatedbyTDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in post-mortem samples from ALS and FTD patients. Proteomics and functional studies illustrated corresponding reductionsin mitochondrial components and compensatory increasesin protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, ultimately causing cell death by disrupting energy production and protein synthesis pathways.
2018-07-25 | GSE115310 | GEO
Project description:Amyotrophic Lateral Sclerosis (ALS) is an adult-onset and fast progression neurodegenerative disease that leads to the loss of motor neurons. Mechanisms of selective motor neuron loss in ALS are unknown. The early events occurring in the spinal cord that may contribute to motor neuron death are not described, neither astrocytes participation in the pre-symptomatic phases of the disease. In order to identify ALS early events, we performed a microarray analysis employing a whole mouse genome platform to evaluate the gene expression pattern of lumbar spinal cords of transgenic SOD1G93A mice and their littermate controls at pre-symptomatic ages of 40 and 80 days. Differentially expressed genes were identified by means of the Bioconductor packages Agi4x44Preprocess and limma. FunNet web based tool was used for analysis of over-represented pathways. Furthermore, immunolabeled astrocytes from 40 and 80 days old mice were submitted to laser microdissection and RNA was extracted for evaluation of a selected gene by qPCR. Statistical analysis has pointed to 492 differentially expressed genes (155 up and 337 down regulated) in 40 days and 1105 (433 up and 672 down) in 80 days old ALS mice. The KEGG pathways tight junction, antigen processing and presentation, oxidative phosphorylation, endocytosis, chemokine signaling pathway, ubiquitin mediated proteolysis and glutamatergic synapse were found over-represented at both 40 and 80 days pre-symptomatic ages. Ube2i gene expression was evaluated in astrocytes from both transgenic ages, being up regulated in 40 and 80 days astrocytes enriched samples. Our data points to important early molecular events occurring in pre-symptomatic phases of ALS in mouse model. Early SUMOylation process linked to astrocytes might account to non autonomous cell toxicity in ALS. Further studies on the signaling pathways presented here may provide new insights to better understand the events triggering motor neuron death in this devastating disorder.
2013-11-21 | GSE50642 | GEO
Project description:Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls. Keywords: other
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Project description:We have identified a novel de novo variation in FUS gene in a sporadic juvenile ALS patient. FUS is an RNA-binding protein actively involved in various aspect of nucleic acid metabolism. We performed RNA-seq to identify altered transcriptome in juvenile ALS.
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Project description:Aim: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood. Methods: Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS-control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected. Results: 245 differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects. Conclusions: Our findings suggest that peripheral blood RNA-seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.
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Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in post-mortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways.
2018-07-24 | PXD009969 | Pride
Project description:Amyotrophic Lateral Sclerosis (ALS) is an adult-onset and fast progression neurodegenerative disease that leads to the loss of motor neurons. Mechanisms of selective motor neuron loss in ALS are unknown. The early events occurring in the spinal cord that may contribute to motor neuron death are not described, neither astrocytes participation in the pre-symptomatic phases of the disease. In order to identify ALS early events, we performed a microarray analysis employing a whole mouse genome platform to evaluate the gene expression pattern of lumbar spinal cords of transgenic SOD1G93A mice and their littermate controls at pre-symptomatic ages of 40 and 80 days. Differentially expressed genes were identified by means of the Bioconductor packages Agi4x44Preprocess and limma. FunNet web based tool was used for analysis of over-represented pathways. Furthermore, immunolabeled astrocytes from 40 and 80 days old mice were submitted to laser microdissection and RNA was extracted for evaluation of a selected gene by qPCR. Statistical analysis has pointed to 492 differentially expressed genes (155 up and 337 down regulated) in 40 days and 1105 (433 up and 672 down) in 80 days old ALS mice. The KEGG pathways tight junction, antigen processing and presentation, oxidative phosphorylation, endocytosis, chemokine signaling pathway, ubiquitin mediated proteolysis and glutamatergic synapse were found over-represented at both 40 and 80 days pre-symptomatic ages. Ube2i gene expression was evaluated in astrocytes from both transgenic ages, being up regulated in 40 and 80 days astrocytes enriched samples. Our data points to important early molecular events occurring in pre-symptomatic phases of ALS in mouse model. Early SUMOylation process linked to astrocytes might account to non autonomous cell toxicity in ALS. Further studies on the signaling pathways presented here may provide new insights to better understand the events triggering motor neuron death in this devastating disorder. Whole lumbar spinal cord from SOD1G93A and Non transgenic controls from 40 and 80 days were used in the experiments. 4 biological replicates were used. A reference sample, comprised by RNA from different neonatal organs (heart, liver, kidney) were used in the hybridations
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Project description:OSE-127 is a humanized monoclonal antibody targeting the IL-7Rα chain (CD127), under development for inflammatory and autoimmune disease treatment. It is a strict antagonist of the IL-7R pathway, is not internalized by target cells and is non-cytotoxic. Here, a first-in-human, phase I, randomized, double-blind, placebo-controlled, single-center study was carried out to determine the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of OSE-127 administration.Sixty-three healthy subjects were randomly assigned to nine groups: six single ascending dose groups with intravenous (IV) administration (0.002-10 mg/kg), a single subcutaneous treatment group (1 mg/kg), and two double IV injection groups (6 or 10 mg/kg). Subjects were followed during < 146 days. OSE-127’s pharmacokinetic half-life after a single dose increased from 4.6 days (1mg/kg) to 11.7 days (10 mg/kg) and, after a second dose, from 12.5 days (6 mg/kg) to 16.25 days (10 mg/kg). Receptor occupancy was ≥ 95% at doses ≥ 0.02 mg/kg and this saturation level was maintained >100 days after two IV infusions at 10 mg/kg. IL-7 consumption was inhibited by OSE-127 administration, as demonstrated by a decreased IL-7 pathway gene signature in peripheral blood cells and by ex-vivo T-lymphocyte restimulation experiments. OSE-127 was well tolerated, with no evidence of cytokine-release syndrome and no significant alteration of blood lymphocyte counts or subset populations.Altogether, the observed lack of significant lymphopenia or serious adverse events, concomitant with the dose-dependent inhibition of IL-7 consumption by target cells highlight that OSE-127 may show clinical activity in IL-7R pathway-involved diseases.
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