Atropa belladonna Expresses a microRNA (aba-miRNA-9497) Highly Homologous to Homo sapiens miRNA-378 (hsa-miRNA-378); both miRNAs target the 3′-Untranslated Region (3′-UTR) of the mRNA Encoding the Neurologically Relevant, Zinc-Finger Transcription Factor ZNF-691
Recent advances in ethnobotanical and neurological research indicate that ingested plants from our diet may not only be a source of nutrition but also a source of biologically relevant nucleic-acid-encoded genetic information. A major source of RNA-encoded information from plants has been shown to be derived from small non-coding RNAs (sncRNAs) such as microRNAs (miRNAs) that can transfer information horizontally between plants and humans. In human hosts, the 3′-untranslated region (3′-UTR) of messenger RNAs (mRNAs) is targeted by these miRNAs to effectively down-regulate expression of that mRNA target in the host CNS. In this paper, we provide evidence that the Atropa belladonna aba-miRNA-9497 (miRBase conserved ID: bdi-miRNA-9497) is highly homologous to the CNS-abundant Homo sapiens miRNA-378 (hsa-miRNA-378) and both target the zinc-finger transcription factor ZNF-691 mRNA 3′-UTR to down-regulate ZNF-691 mRNA abundance. We speculate that the potent neurotoxic actions of the multiple tropane alkaloids of Atropa belladonna may be supplemented by the neuroregulatory actions of aba-miRNA-9497 on ZNF-691, and this may be followed by the modulation in the expression of ZNF-691-sensitive genes. This is the first example of a human brain-enriched transcription factor, ZNF-691, targeted and down-regulated by a naturally occurring plant microRNA, with potential to modulate gene expression in the human CNS and thus contribute to the neurotoxicological-and-psychoactive properties of the Atropa belladonna species of the deadly nightshade Solanaceae family.
KeywordsAtropa belladonna Atropine aba-miRNA-9497 hsa-miRNA-378 Trans-kingdom miRNA signaling Zinc-finger protein ZNF-691
The research in this ‘Perspectives’ article was presented in part at the Vavilov Institute of General Genetics Autumn 2018 Seminar Series (Инcтитyт oбщeй гeнeтики имeни Baвилoвa Oceнь 2018 Ceминap cepии) in Moscow, Russia, October 2018, at the Society for Neuroscience (SFN) Annual Meeting, San Diego USA, November 2018. Sincere thanks are extended to Drs. L. Carver, L. Cong, F. Culicchia, C. Eicken, K. Navel, A.I. Pogue, W. Poon, and the late Drs. J.M. Hill, P.N. Alexandrov, D.R.C. McLachlan, and T.P.A. Kruck for helpful discussions in this research area, for short post-mortem interval (PMI) human brain and retinal tissues or extracts, for initial bioinformatics and data interpretation, and to A.I. Pogue and D. Guillot for expert technical assistance and medical artwork. We would like to further thank the following brain and tissue banks for access to high-quality post-mortem tissues and valuable analytical advice: the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda MD USA; the Oregon Health Sciences University, Portland OR, USA; the Southern Eye Bank, Metairie LA, USA; the University of California (UCI), Irvine CA, USA; and the many neuropathologists, physicians, and researchers in the US and Canada who have provided high-quality, short PMI human brain tissue fractions for scientific analysis. Research on microRNAs, ethnobiology, botanical neurotoxins, pro-inflammatory, and pathogenic signaling in the Lukiw laboratory involving the microbiome, the innate-immune response, amyloidogenesis, synaptogenesis, and neuroinflammation in AD, prion, and in other human neurological- and plant-viroid-based diseases was supported through an unrestricted grant to the LSU Eye Center from Research to Prevent Blindness (RPB); the Louisiana Biotechnology Research Network (LBRN) and NIH grants NEI EY006311, NIA AG18031, and NIA AG038834 (WJL). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging, the National Center for Research Resources, or the National Institutes of Health.
BA performed the original microRNA sequence analysis on Atropa belladonna; BA, WL, and WJL collected, analyzed, and performed bioinformatics analysis and summarized the data and reviewed the current neurologically relevant miRNA literature; YZ, WL, and WJL performed the experiments and were involved in additional data extraction and bioinformatics; WJL wrote the article.
Compliance with Ethical Standards
Conflict of interest
All authors declare that they have no conflict of interest in any of the experiments performed.
This article does not contain any studies with live human participants or animals performed by any of the authors of this manuscript. Human neuronal-glial (HNG) primary cells (Fig. 2e) for all transfection experiments were obtained from commercial sources (Lonza Biosciences, Houston, TX USA); brain gene expression data were derived from archived sources and the references listed in this manuscript; all human cell acquisition and handling procedures involving HNG cells were carried out in strict accordance with the ethics review board policies at donor institutions. The experimental work in this investigative study was reviewed and approved by the Institutional Biosafety Committee/Institutional Review Board (IBC/IRB) in strict accordance with the Institutional Biosafety Committee and the Institutional Review Board Committee (IBC/IRBC) ethical guidelines IBC#18059 and IRBC#6774 at the Louisiana State University Health Sciences Center, New Orleans LA 70112 USA.
- Avsar B, Aliabadi DE (2018) In silico identification of microRNAs in 13 medicinal plants. Turk J Biochem 42(s1):57Google Scholar
- Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J et al (2014) Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 13:397–406. https://doi.org/10.1074/mcp.M113.035600 CrossRefPubMedGoogle Scholar
- Hu H, Rashotte AM, Singh NK, Weaver DB, Goertzen LR, Singh SR, Locy RD (2015) The complexity of posttranscriptional small RNA regulatory networks revealed by in silico analysis of Gossypium arboreum L. leaf, flower and boll small regulatory RNAs. PLoS ONE 10(6):e0127468CrossRefPubMedPubMedCentralGoogle Scholar
- Lee MR (2007) Solanacea IV: atropa belladonna, deadly nightshade. J R Coll Phys Edinb. 37:77–84Google Scholar
- Mallinson T (2010) Deadly nightshade: Atropa Belladonna. Focus First Aid (15): 5. Archived from the original on 2010-05-21Google Scholar
- Marín-Sáez J, Romero-González R, Garrido Frenich A, Egea-González FJ (2018) Screening of drugs and homeopathic products from Atropa belladonna seed extracts: tropane alkaloids determination and untargeted analysis. Drug Test Anal 10:1579–1589. https://doi.org/10.1002/dta.2416 CrossRefPubMedGoogle Scholar
- miRBase; microRNA database; University of Manchester; http://www.mirbase.org/cgi-bin/mirna_summary.pl?fam=MIPF0000081 (last accessed 12 May 2019)
- Pant BD, Musialak-Lange M, Nuc P, May P, Buhtz A, Kehr J, Walther D, Scheible WR (2009) Identification of nutrient-responsive Arabidopsis and rapeseed microRNAs by comprehensive real-time polymerase chain reaction profiling and small RNA sequencing. Plant Physiol 150(3):1541–1555. https://doi.org/10.1104/pp.109.139139 CrossRefPubMedPubMedCentralGoogle Scholar
- Pepeu, G., Giovannini M.G. (2004). “Acetylcholine: I. Muscarinic Receptors”. In Gernot Riedel; Bettina Platt. From messengers to molecules: memories are made of these. Springer. ISBN 978-0-306-47862-8Google Scholar
- Simms PC (2013) Atropa belladonna; https://gardenofgodsandmonsters.wordpress.com/2013/07/17/the-inflexible-unturnable-one-atropa-belladonna/2013;