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The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death

Nature Neuroscience volume 12, pages 618626 (2009) | Download Citation

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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-3β 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.

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Acknowledgements

We thank J. Backer and L.K. Kaczmarek for helpful scientific discussions and D.T. Borst for editorial assistance. This work was supported by US National Institutes of Health grants NS46742 and NS45693 (to R.S.Z.) and by a generous grant from the F.M. Kirby Foundation Program in Neural Repair and Neuroprotection. R.S.Z. is the F.M. Kirby Professor in Neural Repair and Protection.

Author information

Author notes

    • Takahiro Miyawaki
    •  & Dimitry Ofengeim

    These authors contributed equally to this work.

Affiliations

  1. Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Takahiro Miyawaki
    • , Dimitry Ofengeim
    • , Kyung-Min Noh
    • , Adrianna Latuszek-Barrantes
    •  & R Suzanne Zukin
  2. Department of Neurosurgery, Jichi Medical University, Shimotsuke-shi, Tochigi-ken, Japan.

    • Takahiro Miyawaki
  3. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

    • Brian A Hemmings
  4. Department of Pathology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Antonia Follenzi
  5. University of Piemonte Orientale, School of Medicine, Novara, Italy.

    • Antonia Follenzi

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Contributions

T.M. and D.O. designed and conducted the experiments, prepared all of the figures and participated in writing the manuscript. K.-M.N. designed experiments and (with A.F.) provided guidance in the cloning of miRNA and cDNA constructs into the lentiviral vector. A.L.-B. carried out western blot and immunoprecipitation experiments. B.A.H. provided the CTMP constructs. A.F. provided the lentiviral vector and wrote the lentiviral methods. R.S.Z. designed experiments, supervised the study and wrote the manuscript.

Corresponding author

Correspondence to R Suzanne Zukin.

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https://doi.org/10.1038/nn.2299