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

SM Lehmann, C Krüger, B Park, K Derkow… - Nature …, 2012 - nature.com
SM Lehmann, C Krüger, B Park, K Derkow, K Rosenberger, J Baumgart, T Trimbuch, G Eom…
Nature neuroscience, 2012nature.com
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 …
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.
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