Dataset Information

MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers

ABSTRACT: MicroRNAs (miRNAs) are small, non-coding RNAs involved in different cellular functions that have emerged as key regulators of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fatal disease that lacks of not only effective treatments, but also presents delays in its diagnosis, since useful clinical biomarkers are unavailable. In recent years, high-throughput sequencing strategies have appeared to find new ALS biomarkers, to improve early diagnosis and to assess the efficacy of new treatments. Since immortalized lymphocytes obtained from peripheral blood are a suitable model to study pathological features of ALS, we use these samples with the aim of characterize the miRNAs dysregulated in ALS patients. Next-generation sequencing (NGS) was utilized in order to analyse miRNAs expression profiles in immortalized lymphocytes from healthy controls, sporadic ALS (sALS) and familial ALS with mutations in superoxide dismutase 1 (SOD1-ALS). The screening analysis of the NGS data identified a set of dysregulated miRNAs, of which we chose 9 candidates for qRT-PCR validation, identifying for the first time the possible importance of hsa-miR-6821-5p as ALS biomarker.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287831 | GEO | 2026/06/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. To date, multiple panels of biomarkers have been described in ALS patients and murine models. Nevertheless, none of them has sufficient specificity and thus the molecular signature for ALS prognosis and progression remains to be fully elucidated. Circulating microRNAs (miRNAs) are highly stable molecules that are recently used as promising biomarkers for many types of human cancer and muscle disorders. Here we overcome this limitation through a longitudinal study, analyzing serum levels of circulating miRNAs in ALS patients during the progression of the pathology. Method We performed next-generation sequencing (NGS) analysis and absolute RT quantification of serum samples of 27 ALS patients and 11 healthy control; among them 13 ALS patients were studied every three months till the end of the disease. Results We demonstrated that miR-151a-3p, miR-206 and miR-199a-3p are significantly expressed at the mild, moderate and severe stages of ALS pathology, whereas the expression levels of miR-133a and miR-199a-5p remained low during the whole study and retain diagnostic significance in the moderate and severe stages (miR-133a) and in mild and terminal stages (miR-199a-5p) of the disease. Moreover, we analysed the miRNAs serum levels during the progression of the disease in each patient and we demonstrated that high levels of miR-206, miR-133a, miR-151a-5p, miR-151a-3p can predict a slower clinical decline of patient functionality suggesting that these miRNAs represent good potential prognostic markers for ALS disease. Conclusion This study is the first to perform a longitudinal absolute quantification of circulating miRNAs during ALS disease. We highlighted putative biomarkers for diagnosis, prognosis and disease stage identification of ALS patients providing cut-off threshold for most of the miRNAs analyzed. In addition, our results define a molecular signature of ALS phenotypes that could help to define appropriate enrollments of patients in clinical trials.

Project description:Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n=15) and healthy control (n=16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.

Project description:Knowledge about the nature and timepoint of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis (ALS) is largely lacking. It could not only pave the way for valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs (miRNAs) are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained expression profiles of miRNAs as well as other non-coding RNAs (ncRNAs) in the serum of sporadic ALS patients (sALS), familial ALS cases (fALS), asymptomatic mutation carriers and healthy controls. We observed a strikingly homogenous ncRNA profile in fALS patients that, to a large extend, was independent to the underlying disease gene and different to heterogeneous ncRNA signatures in sALS patients. Moreover, we identified 68 significantly dysregulated ncRNAs in pre-manifest ALS mutation carriers, more than 20 years before the estimated time window of disease onset. 91% of ncRNA alterations in mutation carriers overlapped with the fALS patients revealing progressive changes towards and during the disease. Our data thus demonstrate a high epigenetic heterogeneity amongst sALS patients and suggest common denominators regarding molecular pathogenesis of different ALS genes. We describe the earliest pathomolecular alterations in ALS known to date, which provide a basis for the development of predictors of disease onset as well as the discovery of novel therapeutic targets and strongly argue for studies evaluating pre-symptomatic disease-modifying treatment in ALS. Serum ncRNA pofiles of sporadic and familiar ALS patients as well as asymptomatic ALS mutation carriers were compared to age and gender matched healthy controls using a total of 53 Affymetrix miRNA 3.0 arrays. In detail, a total of 9 fALS patients (analyzed in 6 arrays) were compared to 10 controls, a total of 18 ALS mutation carriers (analyzed in 12 arrays) were compared to 8 controls and 18 sALS patients were compared to 16 controls.

Dataset Information

MicroRNA signature of lymphoblasts from amyotrophic lateral sclerosis patients as potential clinical biomarkers

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets