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

被引：617

作者：

Lehmann, Sabrina M. ^{[1
]}

Krueger, Christina ^{[1
]}

Park, Boyoun ^{[2
]}

Derkow, Katja ^{[1
]}

Rosenberger, Karen ^{[1
]}

Baumgart, Jan ^{[3
]}

Trimbuch, Thorsten ^{[4
]}

Eom, Gina ^{[5
]}

Hinz, Michael ^{[6
]}

Kaul, David ^{[1
]}

Habbel, Piet ^{[1
]}

Kaelin, Roland ^{[5
]}

Franzoni, Eleonora ^{[7
]}

Rybak, Agnieszka ^{[6
]}

Nguyen, Duong ^{[7
]}

Veh, Ruediger ^{[8
]}

Ninnemann, Olaf ^{[7
]}

Peters, Oliver ^{[9
]}

Nitsch, Robert ^{[3
]}

Heppner, Frank L. ^{[4
,5
]}

Golenbock, Douglas ^{[10
]}

Schott, Eckart ^{[11
]}

Ploegh, Hidde L. ^{[12
]}

Wulczyn, F. Gregory ^{[7
]}

Lehnardt, Seija ^{[1
,4
,7
]}

机构：

[1] Charite, Dept Neurol, D-13353 Berlin, Germany

[2] Yonsei Univ, Dept Biol, Seoul 120749, South Korea

[3] Johannes Gutenberg Univ Mainz, Inst Microscop Anat & Neurobiol, Mainz, Germany

[4] Charite, Cluster Excellence NeuroCure, D-13353 Berlin, Germany

[5] Charite, Inst Neuropathol, D-13353 Berlin, Germany

[6] Max Delbruck Ctr Mol Med, Berlin, Germany

[7] Charite, Inst Cell Biol & Neurobiol, D-13353 Berlin, Germany

[8] Charite, Ctr Anat, D-13353 Berlin, Germany

[9] Charite, Dept Psychiat, D-13353 Berlin, Germany

[10] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA

[11] Charite, Dept Hepatol & Gastroenterol, D-13353 Berlin, Germany

[12] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

来源：

NATURE NEUROSCIENCE | 2012年 / 15卷 / 06期

关键词：

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

D O I：

10.1038/nn.3113

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：827 / U44

页数：11

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