PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Müller, Martin; Zhou, Jichun; Yang, Lihua; Gao, Yuan; Wu, Fuju; Schoeberlein, Andreina; Surbek, Daniel; Barnea, Eytan R; Paidas, Michael; Huang, Yingqun (2014). PreImplantation factor promotes neuroprotection by targeting microRNA let-7. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 111(38), pp. 13882-13887. National Academy of Sciences NAS 10.1073/pnas.1411674111

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Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, and Alzheimer's disease. Activation of the Toll-like receptor 7 by extracellular microRNA let-7, a highly expressed microRNA in the CNS, induces neuronal cell death. Let-7 released from injured neurons and immune cells acts on neighboring cells, exacerbating CNS damage. Here we show that a synthetic peptide analogous to the mammalian PreImplantation factor (PIF) secreted by developing embryos and which is present in the maternal circulation during pregnancy inhibits the biogenesis of let-7 in both neuronal and immune cells of the mouse. The synthetic peptide, sPIF, destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, s.c. administration of sPIF into neonatal rats following hypoxic-ischemic brain injury robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Our results reveal a previously unexpected mechanism of action of PIF and underscore the potential clinical utility of sPIF in treating hypoxic-ischemic brain damage. The newly identified PIF/TLR4/KSRP/let-7 regulatory axis also may operate during embryo implantation and development.

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