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

作者：Lehmann, Sabrina M.^*; Krueger, Christina; Park, Boyoun; Derkow, Katja; Rosenberger, Karen; Baumgart, Jan; Trimbuch, Thorsten; Eom, Gina; Hinz, Michael; Kaul, David; Habbel, Piet; Kaelin, Roland; Franzoni, Eleonora; Rybak, Agnieszka; Nguyen, Duong; Veh, Ruediger; Ninnemann, Olaf; Peters, Oliver; Nitsch, Robert; Heppner, Frank L.; Golenbock, Douglas; Schott, Eckart; Ploegh, Hidde L.; Wulczyn, F. Gregory; Lehnardt, Seija

来源：Nature Neuroscience, 2012, 15(6): 827-U44.

DOI：10.1038/nn.3113

• ALZHEIMERS-DISEASE
• IMMUNE-RESPONSES
• MICRORNAS
• CELLS
• IDENTIFICATION
• RNA
• INFLAMMATION
• BIOMARKERS
• MICROGLIA
• APOPTOSIS

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.

• 出版日期2012-6