Balkan Journal of Medical Genetics

INVESTIGATION OF CIRCULATING SERUM microRNA-328-3p AND microRNA-3135a EXPRESSION AS PROMISING NOVEL BIOMARKERS FOR AUTISM SPECTRUM DISORDER
Popov NT, Minchev DS, Naydenov MM, Minkov IN, Vachev TI
*Corresponding Author: Assistant Professor Tihomir I. Vachev, Ph.D., Department of Plant Phisyology and Molecular Biology, University of Plovdiv “Paisii Hilendarski,” 24 Tzar Assen Str., Plovdiv, Bulgaria. E-mail: tiho9@abv.bg
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DISCUSSION

There are many reports in the literature for the potential use of miRNAs as biomarkers for neural disorders, such as Parkinson’s and Alzheimer’s disease [10,11]. However, only few studies have been investigating miRNA in serum samples and their importance as biomarkers is still not fully understood. Moreover, the expression profiles of miRNAs in ASD have been examined, including studies from lymphoblastoid cell cultures [12-14]. Exploring the miRNA expression patterns as potential serum-based biomarkers for ASD diagnosis is still in its infancy. The question of how exactly miRNAs regulate their target genes through fine molecular mechanisms in the context of ASD pathogenesis are not fully understood. It is currently known that individual miRNAs can have several target genes, and thus, have an impact on more than one pathway. It was found that miRNAs can regulate translation of a wide range of proteins in neurons [15] including proteins involved in neuronal migration [16], channels [17] and neuronal morphology [18]. A functioning miRNA system is obligatory in astrocytes, with loss of miRNA biogenesis that could lead to seizures and neuro-degeneration [19]. In order to examine the potential role of the two differentially expressed miRNAs, we obtained a list of their validated target genes and constructed a custom script that used the KEGG database for pathways in which the validated target genes participate. Some studies revealed that miR-3135a and miR-328-3p were involved in cancer [20,21]. Moreover, miRNA-328 dysregulation has also been associated with several complex neurological conditions, such as àmyotrophic lateral sclerosis (ALS) [22], Alzheimer’s [23] and prion diseases [24]. At present, there is no scientific data on the role of miR-3135a and miR-328-3p in ASD. Further research is necessary to explore how miR-3135a and miR-328-3p function in ASD. The results of the current study present evidence that addition of circulating biomarker investigations has the potential to improve the specificity of screening and lower the age of diagnosis. Thus, we suggest that an ideal biomarker should be: 1) expressed in the brain tissues, 2) functionally or physiologically related to neurodevelopment, 3) easily measurable, and 4) differentially expressed in subjects diagnosed with ASD. In this study we identified two miRNAs in the serum in accordance with these criteria. The altered miRNAs (miR-3135a and miR-328-3p) presented in this investigation have not been identified in previous ASD research [13,14,25]. Moreover, functional pathway analysis of investigated serum miRNAs uncovered a significant availability of gene networks involved in neuron cellular functions or neurological disorders. The most remarkable findings of our study were that serum miR-3135a and miR-328-3p could discriminate ASD patients from healthy controls. However, the specific pattern of these miRNAs and their appearance in the medical tests as biomarkers requires subsequent confirmation. The discovery of new miRNAs biomarkers for ASD requires the integration of experiments from different fields including: 1) models generated from human tissues allowing for the preservation of individual genetic backgrounds so functional validation in these models may be more relevant than that in animal models, 2) induced pluripotent stem cells (iPSCs) derived neurons are promising models, but these cells have expression signatures more similar to stem cells rather than neurons [26]. Some promising candidates found so far are miR- 132, miR-7 and miR-195. Deregulation of miR-132 was reported in lymphoblastoid cell lines (LCLs) and postmortem cerebellar cortices from ASD patients [26-28]. The biological functions of miR-132 and its targets have been validated by many animal studies [13,29,30]. MiR-7 has been shown to be up-regulated in the saliva and postmortem anterior prefrontal cortices. This miRNA is located in the ASD-associated copy number variation (CNV) locus [31-33] and its functional relevance has been validated using animal studies [34,35]. Deregulation of miR-195 is found in LCLs and serum samples, and it is also disrupted by an ASD-associated CNV locus [25,13]. The role of miRNAs in psychiatric disorders and ASD will be further elaborated using continuously improved relevant approaches. In addition, meta-analysis of miRNAs, covering genetic variation, expression and biological function will provide valuable information for the potential role of miRNA in ASD, and this could help the diagnosis and prognosis of ASD and psychiatric disorders Moreover, miRNA biomarkers could be very useful in distinguishing of different subtypes of psychiatric disorder. Finally, our results contribute to the new course of miRNA research in ASD biology but it is only a small part of the long validation process of miRNA dysregulation in ASD patients.

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