Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 52, Pages 14056-14061Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3399-08.2008
Keywords
ALS; SOD1; angiogenin; motoneuron; hypoxia; neuroprotection
Categories
Funding
- Science Foundation Ireland [03/RP1/B344]
- Enterprise Ireland [PC2005/133, PC2007/045]
- Health Research Board Fellowship and studentship
- Science Foundation Ireland (SFI) [03/RP1/B344] Funding Source: Science Foundation Ireland (SFI)
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Mutations in the hypoxia-inducible factor angiogenin (ANG) have been identified in Amyotrophic Lateral Sclerosis (ALS) patients, but the potential role of ANG in ALS pathogenesis was undetermined. Here we show that angiogenin promotes motoneuron survival both in vitro and in 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-type ANG protected against endoplasmic reticulum (ER) stress-induced and trophic-factor-withdrawal-induced cell death in vitro, whereas the ALS-associated ANG mutant K40I exerted no protective activity and failed to activate Akt-1. In SOD1(G93A) mice 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.
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