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

Item Type:Article
Title:An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration
Creators Name:Lehmann, S.M. and Krueger, C. and Park, B. and Derkow, K. and Rosenberger, K. and Baumgart, J. and Trimbuch, T. and Eom, G. and Hinz, M. and Kaul, D. and Habbel, P. and Kaelin, R. and Franzoni, E. and Rybak, A. and Nguyen, D. and Veh, R. and Ninnemann, O. and Peters, O. and Nitsch, R. and Heppner, F.L. and Golenbock, D. and Schott, E. and Ploegh, H.L. and Wulczyn, F.G. and Lehnardt, S.
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.
Keywords:Alzheimer Disease, Apoptosis, Brain, Confocal Microscopy, Electrophoretic Mobility Shift Assay, HEK293 Cells, Immunohistochemistry, Inbred C57BL Mice, In Situ Hybridization, Knockout Mice, Membrane Glycoproteins, MicroRNAs, Nerve Degeneration, Neurons, Real-Time Polymerase Chain Reaction, Signal Transduction, Toll-Like Receptor 7, Animals, Mice
Source:Nature Neuroscience
ISSN:1097-6256
Publisher:Nature Publishing Group (U.S.A.)
Volume:15
Number:6
Page Range:827-835
Date:June 2012
Official Publication:https://doi.org/10.1038/nn.3113
PubMed:View item in PubMed

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