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

Lehmann, SM;Krger, C;Park, B;Derkow, K;Rosenberger, K;Baumgart, J;Trimbuch, T;Eom, G;Hinz, M;Kaul, D;Habbel, P;Klin, R;Franzoni, E;Rybak, A;Nguyen, D;Veh, R;Ninnemann, O;Peters, O;Nitsch, R;Heppner, FL;Golenbock, D;Schott, E;Ploegh, HL;Wulczyn, FG;Leh

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 Alzheimers 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.

  • PubMed ID: 22610069