Steven D. Hicks1* and Frank A. Middleton2,3,4
1 Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA, 2 Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA, 3 Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA, 4 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide spectrum of deficits in social interaction, communication, and behavior. There is a significant genetic component to ASD, yet no single gene variant accounts for >1% of incidence. Posttranscriptional mechanisms such as microRNAs (miRNAs) regulate gene expression without altering the genetic code. They are abundant in the developing brain and are dysregulated in children with ASD. Patterns of miRNA expression are altered in the brain, blood, saliva, and olfactory precursor cells of ASD subjects. The ability of miRNAs to regulate broad molecular pathways in response to environmental stimuli makes them an intriguing player in ASD, a disorder characterized by genetic predisposition with ill-defined environmental triggers. In addition, the availability and extracellular stability of miRNAs make them an ideal candidate for biomarker discovery. Here, we discuss 27 miRNAs with overlap across ASD studies, including 3 miRNAs identified in 3 or more studies (miR-23a, miR-146a, and miR-106b). Together, these 27 miRNAs have 1245 high-confidence mRNA targets, a significant number of which are expressed in the brain. Furthermore, these mRNA targets demonstrate over-representation of autism-related genes with enrichment of neurotrophic signaling molecules. Brain-derived neurotrophic factor, a molecule involved in hippocampal neurogenesis and altered in ASD, is targeted by 6 of the 27 miRNAs of interest. This neurotrophic pathway represents one intriguing mechanism by which perturbations in miRNA signaling might influence central nervous system development in children with ASD.
Employing miRNAs as Biomarkers
The potential of miRNAs as biomarkers in ASD has been explored in studies of serum and saliva. In a study of serum miRNAs from 55 children with ASD, the authors identified three miRNAs (miR130-3p, miR-181b-5p, and miR-320a) with an area under the curve (AUC) >0.85 (13). In our own more recent study, involving 24 children with ASD, a set of 14 salivary miRNAs showed more than 95% accuracy (AUC = 0.92) at differentiating control and ASD subjects (15). This study also showed that expression patterns of individual salivary miRNAs were significantly correlated with several measures of adaptive behavior. This highlights how the utility of miRNA extends beyond simple ASD diagnosis and may 1 day be used to predict ASD phenotype and severity.
Conclusion
It is clear that miRNA profiles are dysregulated across multiple tissue types in subjects with ASD. This review encapsulated 219 target miRNAs from 12 human studies of ASD and identified 27 that were dysregulated in ≥2 investigations. Functional pathway analysis supports the idea that these miRNAs target brainexpressed genes related to neurodevelopment and implicated in ASD. Three miRNAs showed consistent dysregulation across ≥3 studies (miR-23a-3p, miR-146a-5p, and miR-106b-5p). The networks of genes targeted by these miRNAs are implicated in ASD and have significant roles in neurotrophin signaling. BDNF, which is important for hippocampal neurogenesis and decreased in the serum of adult ASD patients (59), is targeted by 6 of the 27 miRNAs of interest. Animal and cell models that assess these molecular mechanisms behind miRNAs and their mRNA targets will be critical in advancing the current ASD knowledge-base.
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