Synaptosomes secrete and uptake functionally active micro RNA s via exocytosis and endocytosis pathways
Abstract
In this study, we first characterized synaptosome microRNA (miRNA) profiles using microarray and qRT-PCR. MicroRNAs were detected in isolated synaptic vesicles, and Ago2 immunoprecipitation studies revealed an association between miRNAs and Ago2. Second, we found that miR-29a, miR-99a, and miR-125a were significantly elevated in synaptosome supernatants after depolarization. MiRNA secretion by the synaptosome was Ca(2+)-dependent and was inhibited by the exocytosis inhibitor, okadaic acid. Furthermore, application of nerve growth factor increased miRNA secretion without altering the spontaneous release of miRNAs. Conversely, kainic acid decreased miRNA secretion and enhanced the spontaneous release of miRNAs. These results indicate that synaptosomes could secrete miRNAs. Finally, synthesized miRNAs were taken up by synaptosomes, and the endocytosis inhibitor Dynasore blocked this process. After incubation with miR-125a, additional miR-125a was bound to Ago2 in the synaptosome, and expression of the miR-125a target gene (PSD95 mRNA) was decreased; these findings suggest that the ingested miRNAs were assembled in the RNA-induced silencing complex, resulting in the degradation of target mRNAs. To our knowledge, this is the first study that demonstrates the secretion of miRNAs by synaptosomes under physiological stimulation and demonstrates that secreted miRNAs might be functionally active after being taken up by the synaptic fraction via the endocytic pathway.
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miRNAs enter recipient cells by endocytosis and micropinocytosis.
“Indeed, several studies have shown that miRNAs enter recipient cells by endocytosis and micropinocytosis (141, 142).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [141]
Cites
Bartel (2004) · doi:10.1016/s0092-8674(04)00045-5 · Cited by 34,714 · see citing works
Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005) · Cell · doi:10.1016/j.cell.2004.12.035 · Cited by 11,855 · see citing works
Most mammalian mRNAs are conserved targets of microRNAs
Friedman, R. C., Farh, K. K.-H., Burge, C. B., & Bartel, D. P. (2009) · Genome Research · doi:10.1101/gr.082701.108 · Cited by 8,462 · see citing works
Oncomirs — microRNAs with a role in cancer
Esquela‐Kerscher, A., & Slack, F. J. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1840 · Cited by 7,038 · see citing works
MicroRNAs: small RNAs with a big role in gene regulation
He, L., & Hannon, G. J. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1379 · Cited by 5,910 · see citing works
Identification of tissue-specific microRNAs from mouse
Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W., & Tuschl, T. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00809-6 · Cited by 2,859 · see citing works
Gray, E. G., & Whittaker, V. P. (1962) · PubMed · Cited by 2,530 · see citing works
Argonaute2 is the catalytic engine of mammalian RNAi
Liu, J., Carmell, M. A., Rivas, F. V., Marsden, C. G., Thomson, J. M., Song, J.-J., Hammond, S. M., Joshua-Tor, L., & Hannon, G. J. (2004) · Science · doi:10.1126/science.1102513 · Cited by 2,353 · see citing works
Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs
Meister, G., Landthaler, M., Patkaniowska, A., Dorsett, Y., Teng, G., & Tuschl, T. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.07.007 · Cited by 1,718 · see citing works
Koh, J. Y., & Choi, D. W. (1987) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(87)90041-0 · Cited by 1,267 · see citing works
Huttner, W. Β., SCHIEBLER, W., Greengard, P., & Camilli, P. V. D. (1983) · The Journal of Cell Biology · doi:10.1083/jcb.96.5.1374 · Cited by 1,172 · see citing works
A microRNA array reveals extensive regulation of microRNAs during brain development
KRICHEVSKY, A. M., KING, K. S., DONAHUE, C. P., KHRAPKO, K., & KOSIK, K. S. (2003) · RNA · doi:10.1261/rna.5980303 · Cited by 1,040 · see citing works
Cogswell, J. P., Ward, J., Taylor, I. A., Waters, M., Shi, Y., Cannon, B., Kelnar, K., Kemppainen, J., Brown, D., Chen, C., et al. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-14103 · Cited by 943 · see citing works
Diederichs, S., & Haber, D. A. (2007) · Cell · doi:10.1016/j.cell.2007.10.032 · Cited by 687 · see citing works
Keene, J. D., Komisarow, J. M., & Friedersdorf, M. B. (2006) · Nature Protocols · doi:10.1038/nprot.2006.47 · Cited by 612 · see citing works
An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP
Wayman, G. A., Davare, M., Ando, H., Fortin, D., Varlamova, O., Cheng, H.-Y. M., Marks, D., Obrietan, K., Soderling, T. R., Goodman, R. H., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803072105 · Cited by 559 · see citing works
Conditional Loss of Dicer Disrupts Cellular and Tissue Morphogenesis in the Cortex and Hippocampus
Davis, T. H., Cuellar, T. L., Koch, S. M., Barker, A. J., Harfe, B. D., McManus, M. T., & Ullian, E. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4815-07.2008 · Cited by 384 · see citing works
Muddashetty, R. S., Nalavadi, V. C., Gross, C., Yao, X., Xing, L., Laur, O., Warren, S. T., & Bassell, G. J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.05.006 · Cited by 364 · see citing works
Hébert, S. S., Papadopoulou, A. S., Smith, P. Y., Galas, M., Planel, E., Silahtaroglu, A., Sergeant, N., Buée, L., & Strooper, B. D. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq311 · Cited by 323 · see citing works
Baraniskin, A., Kuhnhenn, J., Schlegel, U. S., Chan, A., Deckert, M., Gold, R., Maghnouj, A., Zöllner, H., Reinacher‐Schick, A., Schmiegel, W., et al. (2011) · Blood · doi:10.1182/blood-2010-09-308684 · Cited by 303 · see citing works
MicroRNA Loss Enhances Learning and Memory in Mice
Konopka, W., Kiryk, A., Novak, M., Herwerth, M., Parkitna, J. R., Wawrzyniak, M., Kowarsch, A., Michaluk, P., Dzwonek, J., Arnsperger, T., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3030-10.2010 · Cited by 268 · see citing works
Horizontal transfer of microRNAs: molecular mechanisms and clinical applications
Chen, X., Liang, H., Zhang, J., Zen, K., & Zhang, C. (2012) · Protein & Cell · doi:10.1007/s13238-012-2003-z · Cited by 257 · see citing works
Self-citationKawase‐Koga, Y., Otaegi, G., & Sun, T. (2009) · Developmental Dynamics · doi:10.1002/dvdy.22109 · Cited by 234 · see citing works
Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain
Lugli, G., Torvik, V. I., Larson, J., & Smalheiser, N. R. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05413.x · Cited by 228 · see citing works
Lugli, G., Larson, J., Martone, M. E., Jones, Y., & Smalheiser, N. R. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03224.x · Cited by 222 · see citing works
Spatially restricting gene expression by local translation at synapses
Wang, D. O., Martin, K. C., & Zukin, R. S. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.01.005 · Cited by 187 · see citing works
Huang, T., Liu, Y., Huang, M., Zhao, X., & Cheng, L. (2010) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjq008 · Cited by 173 · see citing works
microRNAs in neurons: manifold regulatory roles at the synapse
Siegel, G., Saba, R., & Schratt, G. M. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.04.008 · Cited by 164 · see citing works
Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology
Lippi, G., Steinert, J. R., Marczylo, E. L., D’Oro, S., Fiore, R., Forsythe, I. D., Schratt, G. M., Zoli, M., Nicotera, P., & Young, K. W. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201103006 · Cited by 145 · see citing works
Dicer is required for survival of differentiating neural crest cells
Zehir, A., Hua, L. L., Maska, E. L., Morikawa, Y., & Cserjesi, P. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.01.039 · Cited by 128 · see citing works
microRNA Regulation of Synaptic Plasticity
Smalheiser, N. R., & Lugli, G. (2009) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8065-2 · Cited by 118 · see citing works
Rapid isolation of synaptoneurosomes and postsynaptic densities from adult mouse hippocampus
Villasana, L., Klann, E., & Tejada-Simon, M. V. (2006) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2006.05.008 · Cited by 117 · see citing works
Kawase‐Koga, Y., Low, R., Otaegi, G., Pollock, A., Deng, H., Eisenhaber, F., Maurer‐Stroh, S., & Sun, T. (2010) · Journal of Cell Science · doi:10.1242/jcs.059659 · Cited by 99 · see citing works
Pichardo‐Casas, I., Goff, L. A., Swerdel, M. R., Athie, A., Davila, J., Ramos-Brossier, M., Lapid-Volosin, M., Friedman, W., Hart, R. P., & Vaca, L. A. (2011) · Brain Research · doi:10.1016/j.brainres.2011.12.001 · Cited by 77 · see citing works
microRNAs: tiny RNA molecules, huge driving forces to move the cell
Huang, S., & He, X. (2010) · Protein & Cell · doi:10.1007/s13238-010-0116-9 · Cited by 28 · see citing works
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Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation
O'Brien, J., Hayder, H., Zayed, Y., & Peng, C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00402 · Cited by 5,287 · see citing works
DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging
Olivieri, F., Albertini, M. C., Orciani, M., Ceka, A., Cricca, M., Procopio, A. D., & Bonafè, M. (2015) · Oncotarget · doi:10.18632/oncotarget.5899 · Cited by 163 · see citing works
Iftikhar, H., & Carney, G. E. (2016) · BioEssays · doi:10.1002/bies.201500130 · Cited by 87 · see citing works
Kumbol, V., Ivanov, A., McGurran, H., Schüler, J., Zhai, Y., Ludwik, K., Hinkelmann, L., Brehm, M., Krüger, C., Küchler, J., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02199-8 · Cited by 8 · see citing works
- Authors
- Xu, J., Chen, Q., Zen, K., Zhang, C., & Zhang, Q.
- Affiliations
- State Key Laboratory of Pharmaceutical Biotechnology (CN)
- Jiangsu Engineering Research Center for Biology and Biotechnology State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University Nanjing Jiangsu China
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2012-11-21
- Volume
- 124
- Issue
- 1
- Pages
- 15-25
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2013749854
- Cited by
- 61
- References
- 35
- Citations by year
- 2025: 3 · 2023: 4 · 2022: 5 · 2021: 10 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 9 · 2016: 2 · 2015: 6 · 2014: 6 · 2013: 5
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30771036, 90608010, 30771039, 30871019, 30890044, 30890032, 30988003, 31071232, 31000323, 31100777)
- National Basic Research Program of China (2011CB504803)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- synaptosomes, microRNA secretion, exocytosis, endocytosis, synaptic vesicles, Argonaute 2, miR-125a, miR-29a, miR-99a, nerve growth factor, kainic acid, calcium-dependent secretion, RNA-induced silencing complex, PSD-95, mRNA degradation, synaptic plasticity
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Brain, Calcium, Endocytosis, Enzyme Inhibitors, Exocytosis, Gene Expression Regulation, L-Lactate Dehydrogenase, Male, Membrane Proteins, Mice, Inbred C57BL, RNA, Messenger, Synaptosomes, Glutamic Acid, Okadaic Acid, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Nerve Growth Factor, MicroRNAs, Microscopy, Electron, Transmission, Synaptotagmin I, Mice, Guanylate Kinases, Metabolic Networks and Pathways, Argonaute Proteins
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