Angiogenin activates the astrocytic Nrf2/antioxidant-response element pathway and thereby protects murine neurons from oxidative stress

Trish T Hoang,Delinda A Johnson,Ronald T Raines,Jeffrey A Johnson

doi:10.1074/jbc.ra119.008491

Abstract

The angiogenin (ANG) gene is mutated frequently in individuals with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. Delivering human ANG to mice that display ALS-like symptoms extends their lifespan and improves motor function. ANG is a secretory vertebrate RNase that enters neuronal cells and cleaves a subset of tRNAs, leading to the inhibition of translation initiation and the assembly of stress granules. Here, using murine neuronal and astrocytic cell lines, we find that ANG triggers the activation of the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway, which provides a critical cellular defense against oxidative stress. This activation, which occurred in astrocytes but not in neurons, promoted the survival of proximal neurons that had oxidative injury. These findings extend the role of ANG as a neuroprotective agent and underscore its potential utility in ALS management.

Highlights

The angiogenin (ANG) gene is mutated frequently in individuals with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the progressive loss of motor neurons
We examined whether ANG activates Nrf2 in cultured cells that were derived from antioxidant-response elements (AREs)–human placental alkaline phosphatase (hPAP) transgenic mice
The ARE drives hPAP expression, which increases the level of human placental alkaline phosphatase

Summary

To whom correspondence may be addressed

Function mutations in the human angiogenin (ANG) gene (4 –6). providing ALS-like transgenic mice that overexpress human SOD1G93A with human ANG increases their lifespan and improves their motor function [7]. Nrf enters the nucleus, where it forms a heterodimer with small Maf proteins This heterodimer binds to antioxidant-response elements (AREs) to drive the expression of antioxidant enzymes that compensate for the physiological and pathophysiological outcomes of oxidant exposure (20 –22). Activation of the Nrf pathway in astrocytes increases neuronal survival [25]. ANG is enriched in motor neurons and protects them against various ALS-related insults, such as excitotoxicity, hypoxia, and endoplasmic reticulum stress [7, 27, 28]. These relationships provoked us to ask: Does ANG activate Nrf2? This activation transmits survivalpromoting signals to proximal neurons, protecting them from oxidative stress

Results

Discussion

Experimental procedures