Antisense MiR-132 Blockade Via the AChE-R Splice Variant Mitigates Cortical Inflammation

Overview

Journal Sci Rep

Specialty Science

Date 2017 Feb 18

PMID 28209997

Citations 14

Authors

Nibha Mishra

Lyndon Friedson

Geula Hanin

Uriya Bekenstein

Meshi Volovich

Estelle R Bennett

David S Greenberg

Hermona Soreq

Affiliations

Soon will be listed here.

Abstract

MicroRNA (miR)-132 brain-to-body messages suppress inflammation by targeting acetylcholinesterase (AChE), but the target specificity of 3'-AChE splice variants and the signaling pathways involved remain unknown. Using surface plasmon resonance (SPR), we identified preferential miR-132 targeting of soluble AChE-R over synaptic-bound AChE-S, potentiating miR-132-mediated brain and body cholinergic suppression of pro-inflammatory cytokines. Inversely, bacterial lipopolysaccharide (LPS) reduced multiple miR-132 targets, suppressed AChE-S more than AChE-R and elevated inflammatory hallmarks. Furthermore, blockade of peripheral miR-132 by chemically protected AM132 antisense oligonucleotide elevated muscle AChE-R 10-fold over AChE-S, and cortical miRNA-sequencing demonstrated inverse brain changes by AM132 and LPS in immune-related miRs and neurotransmission and cholinergic signaling pathways. In neuromuscular junctions, AM132 co-elevated the nicotinic acetylcholine receptor and AChE, re-balancing neurotransmission and reaching mild muscle incoordination. Our findings demonstrate preferential miR-132-induced modulation of AChE-R which ignites bidirectional brain and body anti-inflammatory regulation, underscoring splice-variant miR-132 specificity as a new complexity level in inflammatory surveillance.

Citing Articles

Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis.

Ilieva M Cells. 2024; 13(12.

PMID: 38920691 PMC: 11201512. DOI: 10.3390/cells13121063.

Brain microRNAs are associated with variation in cognitive trajectory in advanced age.

Wingo A, Wang M, Liu J, Breen M, Yang H, Tang B Transl Psychiatry. 2022; 12(1):47.

PMID: 35105862 PMC: 8807720. DOI: 10.1038/s41398-022-01806-3.

Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes.

Stojanovic T, Velarde Gamez D, Schuld G, Bormann D, Cabatic M, Uhrin P Cells. 2022; 11(2).

PMID: 35053378 PMC: 8774101. DOI: 10.3390/cells11020261.

miRNA-132/212 Gene-Deletion Aggravates the Effect of Oxygen-Glucose Deprivation on Synaptic Functions in the Female Mouse Hippocampus.

Bormann D, Stojanovic T, Cicvaric A, Schuld G, Cabatic M, Jan Ankersmit H Cells. 2021; 10(7).

PMID: 34359879 PMC: 8306255. DOI: 10.3390/cells10071709.

Inflammatory signaling mechanisms in bipolar disorder.

Jones G, Vecera C, Pinjari O, Machado-Vieira R J Biomed Sci. 2021; 28(1):45.

PMID: 34112182 PMC: 8194019. DOI: 10.1186/s12929-021-00742-6.

References

Pan Q, Shai O, Lee L, Frey B, Blencowe B . Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008; 40(12):1413-5. DOI: 10.1038/ng.259. View

Ventura A, Young A, Winslow M, Lintault L, Meissner A, Erkeland S . Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008; 132(5):875-86. PMC: 2323338. DOI: 10.1016/j.cell.2008.02.019. View

Yang D, Li T, Wang Y, Tang Y, Cui H, Tang Y . miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression. J Cell Sci. 2012; 125(Pt 7):1673-82. DOI: 10.1242/jcs.086421. View

Strum J, Johnson J, Ward J, Xie H, Feild J, Hester A . MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1. Mol Endocrinol. 2009; 23(11):1876-84. PMC: 5419165. DOI: 10.1210/me.2009-0117. View

Soreq H . Checks and balances on cholinergic signaling in brain and body function. Trends Neurosci. 2015; 38(7):448-58. DOI: 10.1016/j.tins.2015.05.007. View

Li D, Wang A, Liu X, Meisgen F, Grunler J, Botusan I . MicroRNA-132 enhances transition from inflammation to proliferation during wound healing. J Clin Invest. 2015; 125(8):3008-26. PMC: 4563743. DOI: 10.1172/JCI79052. View

Di Giammartino D, Nishida K, Manley J . Mechanisms and consequences of alternative polyadenylation. Mol Cell. 2011; 43(6):853-66. PMC: 3194005. DOI: 10.1016/j.molcel.2011.08.017. View

Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M . Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron. 1993; 10(3):475-89. DOI: 10.1016/0896-6273(93)90335-o. View

Purushotham A, Schug T, Xu Q, Surapureddi S, Guo X, Li X . Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009; 9(4):327-38. PMC: 2668535. DOI: 10.1016/j.cmet.2009.02.006. View

10.

Pasquinelli A . MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012; 13(4):271-82. DOI: 10.1038/nrg3162. View

11.

Meriggioli M, Sanders D . Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009; 8(5):475-90. PMC: 2730933. DOI: 10.1016/S1474-4422(09)70063-8. View

12.

Elwood E, Lim Z, Naveed H, Galea I . The effect of systemic inflammation on human brain barrier function. Brain Behav Immun. 2016; 62:35-40. PMC: 5380128. DOI: 10.1016/j.bbi.2016.10.020. View

13.

Lagos D, Pollara G, Henderson S, Gratrix F, Fabani M, Milne R . miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat Cell Biol. 2010; 12(5):513-9. DOI: 10.1038/ncb2054. View

14.

Lu L, Gasteiger G, Yu I, Chaudhry A, Hsin J, Lu Y . A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner. Immunity. 2015; 43(1):52-64. PMC: 4529747. DOI: 10.1016/j.immuni.2015.04.022. View

15.

Brain O, Owens B, Pichulik T, Allan P, Khatamzas E, Leslie A . The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity. 2013; 39(3):521-36. DOI: 10.1016/j.immuni.2013.08.035. View

16.

Lykhmus O, Mishra N, Koval L, Kalashnyk O, Gergalova G, Uspenska K . Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain. Front Mol Neurosci. 2016; 9:19. PMC: 4781876. DOI: 10.3389/fnmol.2016.00019. View

17.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

18.

Meshorer E, Bryk B, Toiber D, Cohen J, Podoly E, Dori A . SC35 promotes sustainable stress-induced alternative splicing of neuronal acetylcholinesterase mRNA. Mol Psychiatry. 2005; 10(11):985-97. DOI: 10.1038/sj.mp.4001735. View

19.

Hanin G, Shenhar-Tsarfaty S, Yayon N, Yau Y, Hoe Y, Bennett E . Competing targets of microRNA-608 affect anxiety and hypertension. Hum Mol Genet. 2014; 23(17):4569-80. PMC: 4119407. DOI: 10.1093/hmg/ddu170. View

20.

An J, Gharami K, Liao G, Woo N, Lau A, Vanevski F . Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell. 2008; 134(1):175-87. PMC: 2527207. DOI: 10.1016/j.cell.2008.05.045. View