Article abstract
Nature Neuroscience 12, 618 - 626 (2009)
Published online: 6 April 2009 | doi:10.1038/nn.2299
The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death
Takahiro Miyawaki1,2,6, Dimitry Ofengeim1,6, Kyung-Min Noh1, Adrianna Latuszek-Barrantes1, Brian A Hemmings3, Antonia Follenzi4,5 & R Suzanne Zukin1
Abstract
Dysregulation of Akt signaling is important in a broad range of diseases that includes cancer, diabetes and heart disease. The role of Akt signaling in brain disorders is less clear. We found that global ischemia in intact rats triggered expression and activation of the Akt inhibitor CTMP (carboxyl-terminal modulator protein) in vulnerable hippocampal neurons and that CTMP bound and extinguished Akt activity and was essential to ischemia-induced neuronal death. Although ischemia induced a marked phosphorylation and nuclear translocation of Akt, phosphorylated Akt was not active in post-ischemic neurons, as assessed by kinase assays and phosphorylation of the downstream targets GSK-3
and FOXO3A. RNA interference–mediated depletion of CTMP in a clinically relevant model of stroke restored Akt activity and rescued hippocampal neurons. Our results indicate that CTMP is important in the neurodegeneration that is associated with stroke and identify CTMP as a therapeutic target for the amelioration of hippocampal injury and cognitive deficits.
- Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, Bronx, New York, USA.
- Department of Neurosurgery, Jichi Medical University, Shimotsuke-shi, Tochigi-ken, Japan.
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
- Department of Pathology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
- University of Piemonte Orientale, School of Medicine, Novara, Italy.
- These authors contributed equally to this work.
Correspondence to: R Suzanne Zukin1 e-mail: zukin@aecom.yu.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Manganese Superoxide Dismutase Affects Cytochrome c Release and Caspase-9 Activation After Transient Focal Cerebral Ischemia in MiceJournal of Cerebral Blood Flow & Metabolism Original Article
Gender and Strain Influence on Neurogenesis in Dentate Gyrus of Young RatsJournal of Cerebral Blood Flow & Metabolism Original Article
Activation of Akt/Protein Kinase B Contributes to Induction of Ischemic Tolerance in the CA1 Subfield of Gerbil HippocampusJournal of Cerebral Blood Flow & Metabolism Original Article
Serine?Threonine Protein Kinase Akt Does Not Mediate Ischemic Tolerance After Global Ischemia in the GerbilJournal of Cerebral Blood Flow & Metabolism Scientific Correspondence
See all 72 matches for Research
