Title:MicroRNAs: Newcomers into the ALS Picture
VOLUME: 14 ISSUE: 2
Author(s):Cinzia Volonte, Savina Apolloni and Chiara Parisi
Affiliation:Cellular Biology and Neurobiology Institute, CNR, Via del Fosso di Fiorano, 65, 00143 Rome, Italy.
Keywords:Amyotrophic lateral sclerosis, FUS/TLS, miRNA, SOD1-G93A, TDP43.
Abstract:Amyotrophic lateral sclerosis (ALS) causes neurodegeneration of both upper and
lower motor neurons and progressive muscle impairment, atrophy and death within
approximately five years from diagnosis. The aetiology is still not clear but evidence obtained in
animal models of the disease indicates a non-cell-autonomous mechanism with the active
contribution of non-neuronal cells such as microglia, astrocytes, muscle and T cells, which
differently participate to the diverse phases of the disease. Clinically indistinguishable forms of
ALS occur as sporadic disease in the absence of known mutation, or can be initiated by genetic
mutations. About two-third of familial cases are triggered by mutations of four genes that are
chromosome 9 open reading frame 72 (C9ORF72), Cu/Zn superoxide dismutase (SOD1), fused
in sarcoma/translocated in liposarcoma (FUS/TLS), TAR-DNA binding protein 43 (TDP43).
There is at present no succesfull treatment against ALS and the identification of novel signalling pathways, molecular
mechanisms and cellular mediators are still a major task in the search for effective therapies.
MiRNAs are conserved, endogenous, non-coding RNAs that post-transcriptionally regulate protein expression. Produced
as long primary transcripts, they are exported to the cytoplasm and further modified to obtain the mature miRNAs, with
each step of their biogenesis being a potential step of regulation. There are more than 1000 different known human
miRNA sequences, and more than 20-30% of all human protein-coding genes are likely controlled by miRNAs. This earns
to miRNAs the definition of fine regulators of genetic networks. The discovery of the involvement of ALS mutated
proteins TDP43 and FUS/TLS in miRNAs biogenesis strongly suggests a role of miRNA dysregulation also in ALS and
many efforts are thus directed toward understanding the role of these small RNA molecules in the pathogenesis of ALS.
The overall objective of this review is thus to highlight the emerging involvement of miRNAs in ALS. After a brief
description of miRNA biogenesis and function, we discuss the effects of miRNA dysregulation in cellular and molecular
pathways that lead to ALS neuroinflammation and neurodegeneration. In the last part, we focus on the mechanistic
insights of miRNAs that might have implications for the development of novel neuroprotective agents against ALS, and
on recent attempts to establish new molecular miRNA-based therapies. Paving the way for more comparative studies on
neuroinflammatory and neurodegenerative mechanisms, this strategy indeed promises a broader impact on ALS.
