**8. miR-524-5p downregulation**

the miR-9a expression was significantly inhibited [65]. These findings reveal a novel role for endogenous TDP-43 in neuronal specification and suggest that the functions of the FTD/ALSassociated RNA-binding protein TDP-43 ensure the robustness of control genetic programs [65]. Moreover, there is a possibility that TDP-43 may play an important role in miRNA

Though the main feature is the death of motor neurons, other cells contribute to disease like muscle cells. In fact, in ALS animal models it was observed that motor neuron death starts with neuromuscular junction destruction and distal axonal degeneration [67]. The direct partners of the injured motor axons may respectively be the recipients or initiators of the initial damage. The bidirectional signaling between motor neurons and skeletal muscle fibers at neuromuscular synapses has been studied in an animal model. miR-206 is specifically expressed in skeletal muscle and linked to many disorders in skeletal muscle [68]. The expression of miR-206 is regulated by myostatin, TGFβ, and IGF [69, 70]. Moreover, the histone deacetylase 4 and fibroblast growth factor signaling pathways are involved. It was proved that a response to muscle denervation was activated, which promotes skeletal muscle regeneration in response to injury [71–74]. *In vivo* research performed on the ALS model shows the down‐ regulation of miR-206s. This deficiency was correlated with the acceleration of the disease progression [73]. In patients, miR-206 functions like a key factor for muscle reinnervation and disease progression [75]. However, sera from ALS patients showed an increase in the circula‐ tion of miR-206 as well as in SOD1-G93A mouse. Samples from biopsies of Biceps brachii muscle patients with ALS show that miR-206s are overexpressed in the skeletal muscle and plasma of ALS patients [76, 77]. Nevertheless, this miRNA has no enough data about its relation

Quantitative PCR performed on ALS spinal motor neuron samples showed dysregulation of a large number of miRNAs, such as miR-146a and miR-582-3p. An algorithmic program revealed that these miRNAs are able to interact with NFL mRNA 3´UTR and suggested that the main role of these miRNAs is to suppress NFL mRNA [79]. Additional reports on miR-146 function dysregulation are related to the inflammation process by inflammatory factors such as interleukin 1 and tumor necrosis factor-alpha and another process that functions in the innate immune system by regulating Toll-like receptor signaling [80, 81]. On the other hand, *in vitro* experiments performed with mouse neural stem cells showed their relation with proliferation and differentiation, where miR-146 overexpression promoted spontaneous

processing, given an miR-9 downregulation reported on *in vitro* experiments [64].

**6. miR-206 downregulation**

124 Update on Amyotrophic Lateral Sclerosis

with disease status; it has been proposed as a marker [78].

differentiation of neural stem cells by downstream Notch 1 gene [82].

**7. miR-146a downregulation**

Nevertheless, miR-524-5p was inversely associated with the activity of the MAPK/ERK pathway by suppressing the expression of BRAF and ERK2 proteins on melanoma [83], as a tumor suppressor in glioblastoma by Jagged-1 and Hes-1 downregulation [84] and in gastric cancer cells [85]. The results obtained by the application of miRNA recognition element program, on samples obtained from spinal cord neurons of sporadic ALS patients, showed that this miRNA is able to directly regulate the NFL by downregulating its synthesis in neuron cells. However, in ALS patients, it is decreasing and by consequence there is an overproduction of NFL which is a deleterious effect. On the other hand, the overexpression of miR-524-5p inhibits the MAPK/ERK pathway; apparently these cells could demonstrate a high activity on the MAPK/ERK pathway and cytoplasm NS accumulation.
