Active project: miRALS

miRALS
Unravelling the impact of microRNAs on ALS pathogenesis

Two related genes encoding RNA-binding proteins were recently reported in patients with familial ALS: the FUS/TLS gene at the ALS6 locus and the TARDBP/TDP-43 gene at the ALS10 locus. Mutations in these genes corroborate earlier reports of aberrant RNA processing in patients and in murine models of Amyotrophic Lateral Sclerosis (ALS), and strongly suggest that abnormal RNA metabolism may contribute to the pathophysiology of this disease. It is especially noteworthy that both proteins have been implicated in microRNA (miRNA) biogenesis.
MiRNAs are small regulatory non-coding RNA that have the potential to regulate the expression of hundreds of different mRNAs. It has been demonstrated that miRNAs are required for the survival of specific types of mature neurons in model organisms and recent evidence suggests that deregulation of the miRNA regulatory network may be the underlying cause of several different motor neuron diseases. Based on reports of modifications in the expression of miRNAs in the SOD1(G93A) mouse model of ALS and on preliminary data from our laboratory, this study will specifically test the hypothesis that misregulation of miRNA expression is a common feature in familial ALS. To this end we will exploit human neuroblastoma cell lines expressing the SOD1(G93A) mutation, or two ALS-linked mutations in the FUS gene, as tools to investigate the role of miRNAs in familial ALS. The aim of this work is to understand if these modulators of gene expression may play a causative role in disease onset or progression.
Specifically, we propose to
1. Characterize on a genome-wide scale miRNA expression in SH-SY5Y/SOD1(G93A) cells by whole-genome small RNA deep-sequencing;
2. Initiate the functional characterization of the identified, misregulated miRNAs;
3. Generate of SH-SY5Y cells stably expressing wild type or mutant FUS proteins and characterize them for miRNA expression.
Collectively, the proposed project aims at a better understanding of the molecular mechanisms affected in SOD1-linked ALS, with the ultimate goal of unravelling the role of miRNAs in neuronal degeneration and to provide novel targets for diagnosis and therapy of ALS.

Research Team:

Principal Investigator:

Silvia M.L. Barabino