MiR-592 Regulates the Induction and Cell Death-Promoting Activity of p75^NTRin Neuronal Ischemic Injury

Abstract

The neurotrophin receptor p75NTR has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction in pathologic states, there is limited understanding of the mechanisms that regulate p75 NTR expression after injury. Here, we show that after focal cerebral ischemia in vivo or oxygen-glucose deprivation in organotypic hippocampal slices or neurons, p75 NTR is rapidly induced. A concomitant induction of proNGF, a ligand for p75 NTR , is also observed. Induction of this ligand/receptor system is pathologically relevant, as a decrease in apoptosis, after oxygen-glucose deprivation, is observed in hippocampal neurons or slices after delivery of function-blocking antibodies to p75 NTR or proNGF and in p75 NTR and ngf haploinsufficient slices. Furthermore, a significant decrease in infarct volume was noted in p75 NTR Ϫ/Ϫ mice compared with the wild type. We also investigated the regulatory mechanisms that lead to post-ischemic induction of p75 NTR . We demonstrate that induction of p75 NTR after ischemic injury is independent of transcription but requires active translation. Basal levels of p75 NTR in neurons are maintained in part by the expression of microRNA miR-592, and an inverse correlation is seen between miR-592 and p75 NTR levels in the adult brain. After cerebral ischemia, miR-592 levels fall, with a corresponding increase in p75 NTR levels. Importantly, overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p75 NTR and attenuates activation of pro-apoptotic signaling and cell death. These results identify miR-592 as a key regulator of p75 NTR expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury.

Nerve growth factor (NGF)-mediated regulation of p75NTR expression contributes to chemotherapeutic resistance in triple negative breast cancer cells

“…For example, p75 NTR expression is induced in neurons after seizure (13,28), ischemia (15,29) and upon hypo-osmolar stress (14,30,31 (30,32), and both of which are activated by NGF (33,34).…”

“…Transcriptional upregulation of p75 NTR expression has been shown to occur in neurons following brain acute injury (13)(14)(15) …”

MicroRNA regulation in an animal model of acute ocular hypertension

“…Interestingly, the expression change of miR‐592 in our study was highly consistent with that in focal cerebral ischaemia, which suggested that miR‐592 may also influence the apoptosis of retinal ganglion cells in eyes after an acute IOP elevation (Irmady et al. 2014). …”

A Role for the p75 Neurotrophin Receptor in Axonal Degeneration and Apoptosis Induced by Oxidative Stress

“…NTR has been linked to neurodegeneration occurring in models of Alzheimer disease (20), amyotrophic lateral sclerosis (21), and ischemia (22)(23)(24)(25). Therefore, p75 NTR appears to function as a stress-activated receptor that promotes degeneration in response to neuronal injury.…”