The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.

Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases

“…Among the implicated pathological processes are protein aggregation, glutamate excitotoxicity, defects in stress response, mitochondrial dysfunction, protein aggregation, altered axonal transport, and aberrant RNA metabolism [ 199 , 200 , 201 ]. The role of this last, in particular, seems particularly central when considering that several ALS-linked genes, such as TARDBP or FUS , are key components of coding and noncoding RNA processing machinery [ 17 , 202 , 203 , 204 , 205 , 206 , 207 , 208 ].…”

“…MiR-9 plays an important role in regulating MNs development and its differential expression in ALS leukocytes supports its role as a diagnostic biomarker [ 218 , 219 , 220 ] ( Table 3 ). Since it is known to interact with the 3′-UTRs of NEFL and PRPH and Pak4, its dysregulation may affect cell-cell junctions and axonal transport, leading to MN degeneration [ 17 , 218 , 220 , 274 ] ( Table 3 , Figure 2 ). Similar pathogenic mechanisms may follow the dysregulation of the NF-κB-sensitive miR-146a, implicated in the formation of pathological neurofilamentous aggregates [ 215 , 216 , 229 ], neuroinflammation, and immune response [ 55 , 65 , 85 , 86 , 87 , 88 ] ( Table 1 and Table 3 , Figure 1 ).…”

“…Different non-coding RNAs have been proposed as biomarkers of neurodegeneration and, among them, microRNAs (miRNAs) have attracted the scientific community’s attention thanks to their role as key regulators of gene expression [ 14 , 15 , 16 , 17 ]. MiRNAs are short molecules (20–22 nucleotides) able to degrade or inhibit the translation of their multiple complementary mRNA targets in a cell- and tissue-specific manner [ 17 ]. Common target sites for endogenous miRNAs are located in the 3′UTR region of mRNAs where they form an imperfect duplex hybrid and regulate their translation [ 18 ].…”

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

“…miRNAs are transcribed as primary miRNAs, which are subsequently cleaved to precursor miRNAs (pre-miRNAs) and further processed into mature single-stranded ~22-nt miRNAs ( Figure 1 ). The biogenesis of miRNAs requires RNase III enzymes DROSHA and DICER1, members of the Argonaute family (AGO1–4), and RNA polymerase II [ 9 , 10 , 11 ]. Mature miRNAs regulate gene expression by the cleavage of mRNA, translational repression, and the recruitment of epigenetic modifiers such as histone deacetylases (HDACs) and histone methyltransferases (HMT) [ 9 , 10 , 11 ] ( Figure 1 ).…”

“…The biogenesis of miRNAs requires RNase III enzymes DROSHA and DICER1, members of the Argonaute family (AGO1–4), and RNA polymerase II [ 9 , 10 , 11 ]. Mature miRNAs regulate gene expression by the cleavage of mRNA, translational repression, and the recruitment of epigenetic modifiers such as histone deacetylases (HDACs) and histone methyltransferases (HMT) [ 9 , 10 , 11 ] ( Figure 1 ). The deletion of miRNA biogenesis proteins can result in embryonic lethality [ 12 ].…”