**3. miR-338-3 upregulation**

The consequence of that complementary interaction could provide the inhibition of translation or the reduction in the stability of the mRNA resulting in the decrease of the target protein expression [7]. The importance of these small molecules in gene expression has led to numer‐ ous studies, which aimed at better understanding of its functioning as regulators and, in turn, the regulation of transcription. Another characteristic is its possibility to target several mRNAs given a major potential to regulate gene expression or a specific mRNA that can be regulated by multiple miRNAs [8–10]. Although most authors observed a downregulation by miRNAs, there are examples of upregulation by miRNAs as well. The ability of a single miRNA to act both in repression and activation depends on the number of nucleotides that can mate or phase

In order to homogenize the nomenclature of miRNAs for the pre-miRNA and the pri-miRNA, they are referred to as uncapitalized "mir," for the mature form of the miRNA as miR and MIR

Considering the complexity of the capacity and functions of these small molecules, they have been linked to several diseases such as cancer [18, 19], autoimmune diseases [20, 21], cardio‐ vascular diseases [22–26], and, of particular interest to our group, are those related to neuro‐

General reviews on the participation of miRNAs in neurodegenerative diseases have been emerging, and the research on specific neurological diseases confirms a dysregulation biogenesis of these small molecules [27–31]. Impaired concentration of blood miRNAs has been reported in patients with stroke, Alzheimer disease, Huntington disease, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS) [30–46]. In this chapter, ALS disease will be analyzed

The dysregulation of miRNAs in the samples from ALS patients has been reported by several authors. Until now, it is not clear that which one is the most important dysregulation. This chapter aims at analyzing those reports that shed light on the enrolled miRNAs and their

During neuron degeneration in ALS diseases, many alterations on neurofilament have been observed such as the aggregate formation of the perikaryon and proximal axons. In addition, mRNA of low molecular weight neurofilament (NEFL) decreases [47–49]. A number of reports agree that an alteration of NEFL synthesis could contribute to the possible cause of neuron death in ALS patients. Recent reports on the expression analysis of miRNAs, performed on neurons recovered from sporadic ALS patients' spinal cord, confirm the downregulation of miR-b2403 and miR-b1336. These miRNAs modulate NEFL mRNA stability [50]. Consequent‐ ly, it could be the cause of the decreased mRNA, as previously reported in patients with spinal

of the cell cycle in which it is generated [11–16].

for the gene that encodes them [17].

122 Update on Amyotrophic Lateral Sclerosis

logical diseases.

in more detail.

cord ALS.

participation in ALS pathology.

**2. miR-b2403 and miR-b1336 downregulation**

The overexpression of miR-338-3 was reported in leucocytes of ALS patients. This miRNA regulates gene cytochrome *c* oxidase IV [51]. *In vitro* experiments report that the transfection of miR-338 into the axons of primary sympathetic neurons results in a decrease in mitochon‐ drial COXIV mRNAs and consequently a decrease in enzyme protein levels [52]. This protein belongs to the cytochrome *c* oxidase complex, the ending step in the mitochondrial electron transfer chain. Its downregulation results in a decrease in the ATP level and sensitizes the cells to apoptosis [53, 54]. miR-338 also regulates ATP synthase expression, which is another mitochondrial enzyme. The postmortem samples from the frontal cortex of patients with ALS also report on the upregulation of miR-338-3 [55]. The overexpression of miR-338-3 could induce an axonal respiration functionality and viability damage.
