A gene-expression signature in fibroblasts of Amyotrophic Lateral Sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE233881 | GEO | 2024/01/01
REPOSITORIES: GEO
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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
2003-11-14 | GSE833 | GEO
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.
2023-10-12 | GSE234297 | GEO
Project description:Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis and serving as biomarkers of amyotrophic lateral sclerosis (ALS). Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and CSF (cEVs) of sporadic ALS (SALS) patients remain unexplored. This study sought to reveal such changes by collecting serum and CSF at fixed intervals from 10 controls and 20 SALS patients participating in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis trial. We also aimed to reveal longitudinal changes with disease progression and the effects of ropinirole hydrochloride (ROPI, a dopamine D2 receptor agonist identified as an anti-ALS drug candidate using induced pluripotent stem cell drug discovery) on protein profiles of EVs. Comprehensive proteomic analyses of EVs extracted from these samples were conducted using liquid chromatography-mass spectrometry to trace longitudinal shifts linked to disease progression and the influence of ROPI on EV protein profiles. The findings revealed notable disparities but high congruity in sEV and cEV protein profiles concerning disease status, time, and ROPI administration. Moreover, the sEV and cEV protein profiles converged over time in SALS patients, at least in part, suggestive of a loosening of the blood–brain barrier. In SALS patients, both sEVs and cEVs presented elevated inflammation-related protein levels but reduced levels of proteins associated with the unfolded protein response. These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to the unfolded protein response in SALS, suggesting an anti-ALS effect on EV protein profiles. Reverse translational research using induced pluripotent stem cell-derived astrocytes indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. Baseline levels of OGN in sEVs and FRMPD1 in cEVs correlated with subsequent disease progression, indicating their potential as prognostic biomarkers for SALS. Machine learning-driven biomarker searches and diagnostic classification yielded an accuracy of 90.4% for sEVs and 80.3% for cEVs. Despite the limited sample size, this study is the first to report time-series proteomic alterations in sEVs and cEVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.
2024-08-02 | GSE242978 | GEO
Project description:Sporadic amyotrophic lateral sclerosis (sALS) is the most common (~90%) form of ALS. There are no animal models of sALS and exact molecular mechanisms remain elusive. Here, we elucidate gene-expression profiles in laser capture microdissected enriched surviving motor neurons (MNs) from sALS lumbar spinal cords in patients who had rostral onset and caudal progression. A strong signature was detected and immunological signals were computationally filtered. The filtered dataset showed clustering groups that were significantly explained by levels of phosphorylated TDP-43 (pTDP-43). Transcriptome-pathology correlations and enhanced crosslinking and immunoprecipitation combined with sequencing (eCLIP-seq) identified that Casein kinase 1ε (CSNK1E) had the highest correlation with pTDP-43 status and TDP-43 binding in its 3’UTR. Furthermore, CSNK1E interacted with TDP-43 on protein level and its overexpression lead to increased cytoplasmic pTDP-43 accumulations in iPSC-MNs, suggesting CSNK1E directly mediates TDP-43 phosphorylation. Therefore, we report an essential framework for molecular disease classification and transcriptome – pathology correlation in sALS to identify candidate genes for elucidating disease mechanisms and potential therapeutic interventions.
2018-06-06 | GSE103225 | GEO
Project description:Alteration in RNA metabolism, concerning both coding and long non-coding RNAs (lncRNAs), may play an important role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. In this work, we performed RNA-seq analysis to investigate, in Peripheral Blood Mononuclear Cells (PBMC) and spinal cord tissues, the regulation of non-coding and coding RNAs in Sporadic ALS patients (SALS), ALS mutated (FUS, TARDBP and SOD1) patients and matched controls. A total of 293 differentially expressed (DE) lncRNAs were found in SALS patients, as instead a limited amount of lncRNAs was found deregulated in mutated patients. Out of 87 mRNAs detected as differentially expressed in SALS patients, the 10 most differentially expressed were down-regulated and associated to transcription regulation, immunity and apoptosis pathways. 2 Taken together our data highlighted the importance, for the understanding of ALS disease, of extending the knowledge on transcriptome molecular alterations and on the significance in the disease of the classes of regulatory lncRNAs. Our data brought the light on the importance of lncRNAs and mRNAs regulation in central and peripheral systems, offering starting points for new investigations about pathogenic mechanism involved in ALS disease.
2018-04-22 | GSE106443 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE39642: NanoString nCounter immune-related gene expression in blood sorted CD14+CD16- monocytes from sALS, fALS and HC subjects GSE39643: NanoString miRNA profiling of peripheral blood sorted CD14+CD16- monocytes from amyotrophic lateral sclerosis, multiple sclerosis and healthy control subjects Refer to individual Series
2012-07-25 | E-GEOD-39644 | biostudies-arrayexpress
Project description:Amyotrophic lateral sclerosis (ALS) is a clinical subtype of motor neurone disease (MND), a fatal neurodegenerative disease involving the loss of both the upper and lower motor neurones from the motor cortex, brainstem, and spinal cord. Identifying specific disease biomarkers would help to not only improve diagnostic delay but also to classify disease subtypes, monitor response to therapeutic drugs and track disease progression. miRNAs are small non-coding RNA responsible for regulating gene expression and ultimately protein expression and have been used as biomarkers for many cancers and neurodegenerative disorders. Investigating the detection of miRNAs in cerebrospinal fluid (CSF), the fluid that bathes the central nervous system (CNS) is a prime target for identifying potential biomarkers for ALS. This is the first study to investigate the expression of miRNAs in the CSF of ALS patients using small RNA sequencing. We detected differentially expressed miRNAs in the CSF of sporadic ALS (sALS) patients related to neural and glial activity. Additionally, miRNAs involved in glucose metabolism and the regulation of oxidative stress were also identified. Detecting the presence of potential CSF derived miRNA biomarkers in sALS could open up a whole new area of knowledge to help gain a better understanding of disease pathophysiology.
2018-01-09 | GSE105811 | GEO
Project description:This experiment series sought to detect genome-wide methylation in sporadic amyotrophic lateral sclerosis brains and compare it to normal control brains. Methylation across the whole genome was measured in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Array Sets. Methylation calls were compared between SALS patients and controls at each methylated site. Keywords: ChIP-Chip
2009-04-23 | GSE12525 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and still lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex from 51 sporadic ALS patients and 50 control subjects, as well as from four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early disease mechanisms in ALS. An integrated analysis of transcriptomes, (phospho-)proteomes, and miRNAomes revealed marked sex-specific differences, more pronounced in males. We identified four transcriptome-based sALS-subclusters that are driven by pathways involved in mitochondrial respiration, synaptic function, immune response and transcription. Diffusion pseudo time estimation suggested that these clusters may represent temporal states in disease progression. Individual omics and multifactorial factor analysis revealed the mitogen-activated protein kinase (MAPK) pathway as a disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated MEK2 as an auspicious therapeutic target for a subgroup of ALS patients.
2024-05-16 | PXD043297 | Pride
Project description:Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and still lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex from 51 sporadic ALS patients and 50 control subjects, as well as from four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early disease mechanisms in ALS. An integrated analysis of transcriptomes, (phospho-)proteomes, and miRNAomes revealed marked sex-specific differences, more pronounced in males. We identified four transcriptome-based sALS-subclusters that are driven by pathways involved in mitochondrial respiration, synaptic function, immune response and transcription. Diffusion pseudo time estimation suggested that these clusters may represent temporal states in disease progression. Individual omics and multifactorial factor analysis revealed the mitogen-activated protein kinase (MAPK) pathway as a disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated MEK2 as an auspicious therapeutic target for a subgroup of ALS patients.
2024-05-16 | PXD051889 | Pride