MiRNA signature in extracellular vesicles of ALS patients

By Omri Snir
Researcher at TREC

The potential of microRNAs (miRNAs) and extracellular vesicles (EVs) as biomarkers for venous thromboembolism (VTE) and their possible roles in disease pathogenesis are studied in the field of thrombosis, as well as by researchers in TREC. Saucier et al. studied similar questions in amyotrophic lateral sclerosis (ALS) and reported a series of differentially expressed miRNAs that were detected in circulating plasma EVs in comparison with healthy subjects. The potential target genes of such miRNA and the use as biomarkers for prediction of ALS were examined.

ALS, also known as motor neuron disease (MND), is a chronic neurodegenerative disease which causes the death of neurons controlling voluntary muscles. This results in stiff muscles, muscle twitching and gradual worsening of muscle weakness due to decrement in size. The progression of the disease is rather rapid, and eventually patients cannot control their limbs, lose the ability to speak and swallow food and to breath on their own. Currently, there is no cure for ALS and most patients die within 2-4 years following diagnosis.

MiRNAs are small non-coding RNA molecules containing about 22 nucleotides, found in plants, animals and some viruses and function in post-transcriptional regulation of gene expression, e.g. RNA silencing. The human genome may encode over 600 miRNAs which are believed to target about 60% of all genes. MiRNAs circulating in plasma are mostly bound to proteins (i.e. AGO protein family) or found in EVs that are shed from cells, which can be found in all body fluids.

In the study, miRNA was extracted specifically from EVs isolated from plasma and further sequenced. Samples were collected from fourteen ALS patients and twelve healthy controls. Higher expression levels of five miRNAs were found in ALS patients in comparison to the controls, whereas twenty-two miRNAs were expressed at lower levels. Gene targets were predicted for all differentially expressed miRNAs, and in order to find possible pathways and processes that may play a role, functional gene ontology (GO) was performed. Transcriptional regulation and protein ubiquitination were significantly associated with genes targeted by ALS-associated miRNAs. Prediction models highlighted miR-15a-5p and MiR-193a-5p for their diagnostic potential and association with disease-associated disabilities, respectively.

In summary, the study demonstrates the potential of EV-encapsulated circulating miRNA in prediction of disease and disease progression. The study, however, is rather small and the findings were not replicated. Also, the prediction models represent a simplistic approach. Nonetheless, it could be used as a model for similar, yet more solid studies in other diseases, including VTE.

Reference: Saucier et al. Identification of a circulating miRNA signature in extracellular vesicles collected from amyotrophic lateral sclerosis patients. Brain Res. 2019.

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