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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00288

Dysregulation of microRNAs and Target Genes Networks in Peripheral Blood of Patients with Sporadic Amyotrophic Lateral Sclerosis.

  • 1Biomedicine, Institute of Biomedical Technologies, Bari Unit, Consiglio Nazionale Delle Ricerche (CNR), Italy
  • 2Department of Basic Sciences, Neurosciences and Sense Organs, Università degli Studi di Bari, Italy

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease. While genetics and other factors contribute to ALS pathogenesis, critical knowledge is still missing and validated biomarkers for monitoring the disease activity have not yet been identified. To address those aspects we performed this study with the primary aim of identifying possible miRNAs/mRNAs dysregulation associated with the sporadic form of the disease (sALS). Additionally, we explored miRNAs as modulating factors of the observed clinical features.
Study included 56 sALS and 20 healthy controls (HC). We analyzed the peripheral blood samples of sALS patients and HC with a High-Throughput Next-generation Sequencing followed by an integrated bioinformatics/biostatistics analysis. Results showed that 38 miRNAs (let-7a-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-103a-3p, miR-106b-3p, miR-128-3p, miR-130a-3p, miR-130b-3p, miR-144-5p, miR-148a-3p, miR-148b-3p, miR-15a-5p, miR-15b-5p, miR-151a-5p, miR-151b, miR-16-5p, miR-182-5p, miR-183-5p, miR-186-5p, miR-22-3p, miR-221-3p, miR-223-3p, miR-23a-3p, miR-26a-5p, miR-26b-5p, miR-27b-3p, miR-28-3p, miR-30b-5p, miR-30c-5p, miR-342-3p, miR-425-5p, miR-451a, miR-532-5p, miR-550a-3p, miR-584-5p, miR-93-5p) were significantly downregulated in sALS. We also found that different miRNAs profiles characterized the bulbar/spinal onset and the progression rate. This observation supports the hypothesis that miRNAs may impact the phenotypic expression of the disease. Genes known to be associated with ALS (e.g. PARK7, C9orf72, ALS2, MATR3, SPG11, ATXN2) were confirmed dysregulated in our study, as well as we identified other potential candidate genes like LGALS3 (implicated in neuroinflammation) and PRKCD (activated in mitochondrial-induced apoptosis). Some of the downregulated genes are involved in molecular bindings to ions (i.e. metals, zinc, magnesium) and in ions-related functions. The genes that we found upregulated genes involved in the immune response, oxidation-reduction and apoptosis.
These findings may have important implication for the monitoring e.g. of sALS progression and therefore represent a significant advance in the elucidation of the disease’s underlying molecular mechanisms. The extensive multidisciplinary approach we applied in this study was critically important for its success, especially in complex disorders such as sALS, wherein access to genetic background is a major limitation.

Keywords: Sporadic amyotrophic lateral sclerosis, microRNA, Target genes, Peripheral blood markers, High Throughput Next-generation Sequencing (HT-NGS), bioinformatics, pathway analysis.

Received: 19 May 2018; Accepted: 31 Jul 2018.

Edited by:

Giuseppe Filomeni, Danish Cancer Society, Denmark

Reviewed by:

Eva M. Jimenez-Mateos, Royal College of Surgeons in Ireland, Ireland
Harshini Sarojini, University of Louisville, United States  

Copyright: © 2018 Liguori, Nuzziello, Introna, Consiglio, Licciulli, D'Errico, Scarafino, Distaso and Simone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Maria Liguori, Consiglio Nazionale Delle Ricerche (CNR), Biomedicine, Institute of Biomedical Technologies, Bari Unit, Rome, 70125, Italy, maria.liguori@cnr.it