Unknown,Transcriptomics,Genomics,Proteomics

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MiRNome profiling of sporadic ALS patients

ABSTRACT: We aimed to identify muscle-specific common miRNA profile associated with the etiopathogenesis of sporadic ALS (sALS). For this purpose, we isolated total RNA from the skeletal muscle tissues of 10 sALS patients and 5 control individuals, and miRNA expression of sALS patients and controls were analyzed using Affymetrix GeneChip miRNA 4.0 Array. In order to find out differentially expressed miRNAs, we used The Institute for Genomic Research-Multi Experiment Viewer(MeV) tool. Differentially expressed miRNAs that were found to be statistically significant (with parameters, fold change ≥2.0, and FDR=0 for MeV-SAM analysis) were identified as the potential miRNA candidates.

ORGANISM(S): Homo sapiens

SUBMITTER: Burcu Balsci Hayta

PROVIDER: E-MTAB-9140 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

Project description:Loss of muscle proteins and the consequent weakness has important clinical consequences in diseases such as cancer, diabetes, chronic heart failure and in ageing. In fact, excessive proteolysis causes cachexia, accelerates disease progression and worsens life expectancy. Muscle atrophy involves a common pattern of transcriptional changes in a small subset of genes named atrophy-related genes or atrogenes. Whether microRNAs play a role in the atrophy program and muscle loss is debated. To understand the involvement of miRNAs in atrophy we performed miRNA expression profiling of mouse muscles under wasting conditions such as fasting, denervation, diabetes and cancer cachexia. We found that the miRNA signature is peculiar of each catabolic condition. We then focused on denervation and we revealed that changes in transcripts and microRNAs expression did not occur simultaneously but were shifted. Indeed, while the transcriptional control of the atrophy-related genes peaks at 3 days, the changes of miRNA expression maximised at 7 days after denervation. Among the different miRNAs, microRNA-206 and 21 were the most induced in denervated muscles. We characterized their pattern of expression and defined their role in muscle homeostasis. Indeed, in vivo gain and loss of function experiments revealed that miRNA-206 and miRNA-21 were sufficient and required for atrophy program. In silico and in vivo approaches identified the transcription factor YY1 and the translational initiator factor eIF4E3 as downstream targets of these miRNAs. Thus miRNAs are important for the fine-tuning of the atrophy program and their modulation can be a novel potential therapeutic approach to counteract muscle loss and weakness in catabolic conditions. To determine which miRNAs are relevant for the atrophic process, we performed miRNA expression profiles of muscles from different atrophic models (starvation, denervation and streptozotocin-induced diabetes). We checked whether there was a common signature of miRNA expression in different atrophying conditions and we found that every catabolic situation require a peculiar pattern of miRNA. We further focus on the condition of denervation and identified the most up-regulated miRNAs in this condition, miRNA-206 and miRNA-21.

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MiRNome profiling of sporadic ALS patients

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