Maria Teresa Gonzalez Garza

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62989

#### **Abstract**

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miRNAs are sequences of 20–22 nucleotides that participate in the development, growth, and cell differentiation by the regulation of the mRNAs.Their possible participation in the development of degenerative diseases has been extensively investigated. Results show quantitative changes in miRNA transcription, to the pathogenesis of various neurodegenerative diseases. In this chapter, the dysregula‐ tion of microRNAs reported in the samples taken from amyotrophic lateral sclerosis (ALS) animal model or ALS patients is analyzed. Moreover,their probable participa‐ tion in the pathogenesis of the disease is also analyzed.

**Keywords:** ALS, microRNA, miR-206, miR-338-3, miR-9a

## **1. Introduction**

miRNAs are small RNA molecules that do not encode proteins. They are sequences of 20–22 nucleotides that regulate gene expression. miRNAs were identified in 1993 by Lee et al. [1]. Since then numerous studies have been carried out in order to have a better understanding of their functioning as regulators and, in turn, regulating transcription. These molecules are transcribed as a longer RNA between 500 and 3000 nucleotides [2, 3]. Then, a serial enzymat‐ ic activity inside the nucleus allows the reduction in the number of nucleotides. These primiRNAs are then exposed to an enzymatic process by using Drosha-associated Pasha (also known as DGCR8), resulting in a precursor of 65–75 nucleotides in a loop called pre-miR‐ NA, which is transported to the cytoplasm. Finally, the Dicer enzyme breaks for mature singlestranded fragments comprise 19–25 nucleotides. The last enzymatic activity into cytoplasm provides an miRNA of 20–22 nucleotides with a complementary sequence of seven base pairs that enable an miRNA to bind to the target mRNA [3–6].

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

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 for the gene that encodes them [17].

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‐ logical diseases.

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 in more detail.

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 participation in ALS pathology.

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

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 cord ALS.
