MicroRNAs analysis of patient-derived iPSCs as molecular therapy for ALS

author: Monica Nizzardo, Dino Ferrari Centre
published: July 21, 2017,   recorded: May 2017,   views: 888


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Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by progressive degeneration of motor neurons (MNs). The mechanisms underlying the disease and specific proteins involved are almost unknown, even if the dysregulation in RNA metabolism represents a major contributor to ALS aetiology. Mutations in genes encoding for DNA/RNA-binding proteins, such as TDP-43 and FUS, and the hexanucleotide intronic repeat expansions in C9ORF72 have been associated with familial ALS (fALS) and represent the first genetic cause of sporadic ALS (sALS). In particular, TDP-43 and FUS have been implicated in several steps of RNA metabolism, including microRNA (miRNA) processing. MiRNA are tissue-specific small molecules that can individually regulate several hundred targets by RNA-dependent mechanism. Since miRNAs are required for the survival of specific types of mature neurons in model organisms, they may play important roles in the aetiology or progression of neurodegenerative disorders. We and other groups have demonstrated that ALSlinked genes can affect miRNA expression. Here we aim to investigate the role of miRNAs dysregulation and their relative proteomic changes in induced pluripotent stem cells (iPSCs) derived from fALS/sALS patients, based on in vitro models developed in our lab. We performed Next Generation Sequencing (NGS) analysis on iPSC-derived motor neurons in order to identify dysregulated miRNAs in ALS and we further characterized them and their biological targets by bioinformatic tools, molecular and proteomic studies in vitro and in vivo. This approach can increase the chances of modifying complex diseases, such as ALS, by targeting the entire gene networks. Moreover, the identification of feasible miRNAs as targets of the disease can lead to the discovery of new disease biomarkers and therapeutic strategies.

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