An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration

Sabrina M. Lehmann, Christina Krüger, Boyoun Park, Katja Derkow, Karen Rosenberger, Jan Baumgart, Thorsten Trimbuch, Gina Eom, Michael Hinz, David Kaul, Piet Habbel, Roland Kälin, Eleonora Franzoni, Agnieszka Rybak, Duong Nguyen, Rüdiger Veh, Olaf Ninnemann, Oliver Peters, Robert Nitsch, Frank L. HeppnerDouglas Golenbock, Eckart Schott, Hidde L. Ploegh, F. Gregory Wulczyn, Seija Lehnardt

Research output: Contribution to journalArticle

384 Citations (Scopus)

Abstract

Activation of innate immune receptors by host-derived factors exacerbates CNS damage, but the identity of these factors remains elusive. We uncovered an unconventional role for the microRNA let-7, a highly abundant regulator of gene expression in the CNS, in which extracellular let-7 activates the RNA-sensing Toll-like receptor (TLR) 7 and induces neurodegeneration through neuronal TLR7. Cerebrospinal fluid (CSF) from individuals with Alzheimer's disease contains increased amounts of let-7b, and extracellular introduction of let-7b into the CSF of wild-type mice by intrathecal injection resulted in neurodegeneration. Mice lacking TLR7 were resistant to this neurodegenerative effect, but this susceptibility to let-7 was restored in neurons transfected with TLR7 by intrauterine electroporation of Tlr7 -/- fetuses. Our results suggest that microRNAs can function as signaling molecules and identify TLR7 as an essential element in a pathway that contributes to the spread of CNS damage.

Original languageEnglish
Pages (from-to)827-835
Number of pages9
JournalNature Neuroscience
Volume15
Issue number6
DOIs
Publication statusPublished - 2012 Jun 1

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Lehmann, S. M., Krüger, C., Park, B., Derkow, K., Rosenberger, K., Baumgart, J., Trimbuch, T., Eom, G., Hinz, M., Kaul, D., Habbel, P., Kälin, R., Franzoni, E., Rybak, A., Nguyen, D., Veh, R., Ninnemann, O., Peters, O., Nitsch, R., ... Lehnardt, S. (2012). An unconventional role for miRNA: Let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nature Neuroscience, 15(6), 827-835. https://doi.org/10.1038/nn.3113