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RESEARCH PRODUCT

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

Douglas T. GolenbockSeija LehnardtMichael HinzF. Gregory WulczynOliver PetersDavid KaulBoyoun ParkJan BaumgartAgnieszka RybakEleonora FranzoniEckart SchottThorsten TrimbuchKatja DerkowDuong T. T. NguyenFrank L. HeppnerChristina KrügerHidde L. PloeghRobert NitschGina D. EomRüdiger W. VehRoland E. KälinOlaf NinnemannPiet HabbelSabrina M. LehmannKaren Rosenberger

subject

Cell signalingApoptosisElectrophoretic Mobility Shift AssayBiologyReal-Time Polymerase Chain ReactionMiceAlzheimer DiseasemicroRNAExtracellularmedicineAnimalsHumansReceptorIn Situ HybridizationMice KnockoutNeuronsToll-like receptorMembrane GlycoproteinsMicroscopy ConfocalInnate immune systemGeneral NeuroscienceNeurodegenerationBrainvirus diseasesTLR7medicine.diseaseImmunohistochemistryMice Inbred C57BLMicroRNAsHEK293 CellsToll-Like Receptor 7Nerve DegenerationCancer researchSignal Transduction

description

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.

yearjournalcountryeditionlanguage
2011-12-27Nature Neuroscience
https://doi.org/10.1038/nn.3113