Serum microRNA profiles and autism

I cannot pretend to be an expert on microRNA (miRNA). Indeed, it was only after reading the paper by Mahesh Mundalil Vasu and colleagues [1] (open-access) talking about serum microRNA profiles in children diagnosed with an autism spectrum disorder (ASD), that I started my learning journey about these small non-coding RNAs. So please, go easy with me on this one...

Hamlet @ Wikipedia 

Quite a good [short] introduction to microRNAs can be found here. If you want something a little more comprehensive then I might direct you to the paper by Bartel which can be found here [2] (open-access). Basically, miRNAs are a type of post-transcriptional regulator. "Once made, miRNAs can suppress gene expression by inhibiting translation or promoting mRNA degradation". There you have some hints as to why miRNAs might be quite important; as Vasu and colleagues put it: "MicroRNAs (miRNAs) have recently emerged as prominent epigenetic regulators of a variety of cellular processes, including differentiation, apoptosis and metabolism".

A few details from the Vasu paper might be useful, bearing in mind the paper is open-access and snippets of the findings were reported at IMFAR 2014:

• "Total RNA, including miRNA, was extracted from the serum samples of 55 individuals with ASD and 55 age- and sex-matched control subjects, and the mature miRNAs were selectively converted into cDNA". The average of participants in both groups was around 11 years old.
• Screening was undertaken looking at the expression and quantification of miRNAs to determine whether there were any differences between autism and control groups. Further analysis was completed "to predict the target genes and altered pathways of differentially expressed miRNAs".
• Results: "In the preliminary array screening, we observed an altered expression of 14 miRNAs in the ASD samples compared to those of controls". Some miRNAs were up-regulated; others down-regulated. Some 'fine-tuning' of this list of miRNAs differentially expressed in the autism group ended up with 13 miRNAs. Analysis of the genetic targets of these MiRNAs came up with several possible relations - "600 predicted genes and 18 neurological pathways" - but the top 10 neurological pathways covered "axon guidance, TGF-beta signaling, MAPK signaling, adherens junction, regulation of actin cytoskeleton, oxidative phosphorylation, hedgehog signaling, focal adhesion, mTOR signaling and Wnt signaling". Some of these processes have been talked about previously with autism in mind, for example, as per the article by Wang & Doering [3] on mTOR and autism (see also a previous post on this blog). mTOR is also enjoying some even more recent coverage too [4].
• Based on scores for the autism group derived from the ADI-R (Autism Diagnostic Interview - Revised), researchers did not find any significant correlations between miRNA expressions and the core behavioural domains. 
• The authors did [tentatively] suggest that: "Five miRNAs showed good predictive power for distinguishing individuals with ASD". We'll see how this pans out in future work...

MicroRNAs have been talked about with autism in mind previously in the peer-reviewed literature. The paper by Vaishnavi and colleagues [5] (open-access) for example, talked about SNPs (single nucleotide polymorphisms) "perturbing miRNA-mediated gene regulation [that] might lead to aberrant expression of autism-implicated genes". Indeed, they identified "9 MRE [miRNA recognition elements] -modulating SNPs and another 12 MRE-creating SNPs in the 3'UTR of autism-implicated genes". Certainly this work might put those 'common genetic variants' into something of a new light.

Ziats & Rennert [6] in their discussions about "differentially expressed microRNAs across the developing human brain" talked about miRNAs potentially being linked to a variety of neurodevelopmental conditions. Schizophrenia and autism were the conditions talked about by Mellios & Sur [7], with the lion's share of work currently going to schizophrenia [8] over autism. That being said, I'd wager that there will be more to see from research looking at miRNAs and autism in the coming years especially when Vasu et al reported: "The differentially expressed miRNAs in this study... were previously reported to have altered expression in schizophrenia... supporting the contention that ASD and schizophrenia share common neurobiological features". Common ground indeed.

I'm still getting my head around miRNAs and autism, and by no means should this entry be viewed as anything other than an amateur attempt to explain them and their potential importance to autism and various other conditions [9]. The Vasu results, whilst preliminary, offer a good roadmap to further investigation being undertaken bearing in mind the various other areas being examined beyond just traditional genomics and the very important focus on gene expression. Now, about miRNAs and comorbidity like ADHD [10]...

Music then, and how about a spot of Johnny Cash and I Walk the Line.

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[1] Vasu MM. et al. Serum microRNA profiles in children with autism. Molecular Autism. 2014; 5: 40

[2] Bartel DP. MicroRNAs: Genomics, Biogenesis, Mechanism, and Function. Cell. 2004; 116: 281-297.

[3] Wang H. & Doering LC. Reversing autism by targeting downstream mTOR signaling. Front Cell Neurosci. 2013 Mar 26;7:28.

[4] Tang G. et al. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron. 2014. August 21.

[5] Vaishnavi V. et al. Mining the 3'UTR of autism-implicated genes for SNPs perturbing microRNA regulation. Genomics Proteomics Bioinformatics. 2014 Apr;12(2):92-104.

[6] Ziats MN. & Rennert OM. Identification of differentially expressed microRNAs across the developing human brain. Mol Psychiatry. 2014 Jul;19(7):848-52.

[7] Mellios N. & Sur M. The Emerging Role of microRNAs in Schizophrenia and Autism Spectrum Disorders. Front Psychiatry. 2012 Apr 25;3:39.

[8] Sun E. & Shi Y. MicroRNAs: small molecules with big roles in neurodevelopment and diseases. Experimental Neurology. 2014. August 13.

[9] Ru Y. et al. The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res. 2014 Jul 24. pii: gku631.

[10] Kandemir H. et al. Evaluation of miR18a-5p, miR22-3p, miR24-3p, miR106b-5p, miR107, miR125b-5p, and miR155a-5p levels in children and adolescents with attention deficit hyperactivity disorder. Neuroscience Letters. 2014. August 12.

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Mundalil Vasu, M., Anitha, A., Thanseem, I., Suzuki, K., Yamada, K., Takahashi, T., Wakuda, T., Iwata, K., Tsujii, M., Sugiyama, T., & Mori, N. (2014). Serum microRNA profiles in children with autism Molecular Autism, 5 (1) DOI: 10.1186/2040-2392-5-40