Control of Motoneuron Survival by Angiogenin
- Dairín Kieran1,*,
- Jordi Sebastia1,*,
- Matthew J. Greenway2,
- Matthew A. King1,
- Dervla Connaughton1,
- Caoimhin G. Concannon1,
- Beau Fenner1,
- Orla Hardiman3, and
- Jochen H. M. Prehn1
- 1Department of Physiology and Medical Physics and Royal College of Surgeons in Ireland (RCSI) Neuroscience Research Centre, RCSI, Dublin 2, Ireland,
- 2National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland, and
- 3Department of Neurology, Beaumont Hospital, Dublin 11, Ireland
- Correspondence should be addressed to Prof. Jochen H. M. Prehn, Department of Physiology and Medical Physics and RCSI Neuroscience Research Centre, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. prehn{at}rcsi.ie
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↵*D.K. and J.S. contributed equally to this work.
Abstract
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 SOD1G93A 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.
- Copyright © 2008 Society for Neuroscience 0270-6474/08/2814056-06$15.00/0
