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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy*
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Androstadienes / pharmacology
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Disease Models, Animal
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Female
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Gene Expression / drug effects
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Insulin-Like Growth Factor I / pharmacology
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Intercellular Adhesion Molecule-1 / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Neurons / drug effects*
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Mutagenesis, Site-Directed / methods
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Neuroprotective Agents / pharmacology*
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Oncogene Protein v-akt / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Ribonuclease, Pancreatic / genetics
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Ribonuclease, Pancreatic / metabolism*
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Ribonuclease, Pancreatic / pharmacology*
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Ribonuclease, Pancreatic / therapeutic use
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Spinal Cord / cytology
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Superoxide Dismutase / genetics
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Time Factors
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Transfection / methods
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Tunicamycin / pharmacology
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Wortmannin
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Androstadienes
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Neuroprotective Agents
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RNA, Small Interfering
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Tunicamycin
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Intercellular Adhesion Molecule-1
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Insulin-Like Growth Factor I
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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SOD1 G93A protein
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Superoxide Dismutase
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Oncogene Protein v-akt
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angiogenin
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Ribonuclease, Pancreatic
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Wortmannin