Control of Motoneuron Survival by Angiogenin

Mutations in the hypoxia-inducible factor angiogenin (ANG) have been identified in Amyotrophic Lateral Sclerosis (ALS) patients, but the potential role ofANGin ALS pathogenesis was undetermined. Here we show that angiogenin promotes motoneuron survival bothin vitroandin vivo. Angiogenin protected cultured motoneurons against excitotoxic injury in a PI-3-kinase/Akt kinase-dependent manner, whereas knock-down of angiogenin potentiated excitotoxic motoneuron death. Expression of wild-typeANGprotected against endoplasmic reticulum (ER) stress-induced and trophic-factor-withdrawal-induced cell deathin vitro, whereas the ALS-associatedANGmutant K40I exerted no protective activity and failed to activate Akt-1. InSOD1G93Amice angiogenin delivery increased lifespan and motoneuron survival, restored the disease-associated decrease in Akt-1 survival signaling, and reversed a pathophysiological increase in ICAM-1 expression. Our data demonstrate that angiogenin is a key factor in the control of motoneuron survival.