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

Takahiro Miyawaki, Dimitry Ofengeim, Kyung Min Noh, Adrianna Latuszek-Barrantes, Brian A. Hemmings, Antonia Follenzi, R. Suzanne Zukin

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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.

Original languageEnglish (US)
Pages (from-to)618-626
Number of pages9
JournalNature Neuroscience
Volume12
Issue number5
DOIs
StatePublished - May 2009

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Ischemia
Proteins
Neurons
Stroke
Phosphorylation
Glycogen Synthase Kinase 3
Brain Diseases
RNA Interference
Heart Diseases
Phosphotransferases
Wounds and Injuries
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Miyawaki, T., Ofengeim, D., Noh, K. M., Latuszek-Barrantes, A., Hemmings, B. A., Follenzi, A., & Zukin, R. S. (2009). The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. Nature Neuroscience, 12(5), 618-626. https://doi.org/10.1038/nn.2299

The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. / Miyawaki, Takahiro; Ofengeim, Dimitry; Noh, Kyung Min; Latuszek-Barrantes, Adrianna; Hemmings, Brian A.; Follenzi, Antonia; Zukin, R. Suzanne.

In: Nature Neuroscience, Vol. 12, No. 5, 05.2009, p. 618-626.

Research output: Contribution to journalArticle

Miyawaki, T, Ofengeim, D, Noh, KM, Latuszek-Barrantes, A, Hemmings, BA, Follenzi, A & Zukin, RS 2009, 'The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death', Nature Neuroscience, vol. 12, no. 5, pp. 618-626. https://doi.org/10.1038/nn.2299
Miyawaki T, Ofengeim D, Noh KM, Latuszek-Barrantes A, Hemmings BA, Follenzi A et al. The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. Nature Neuroscience. 2009 May;12(5):618-626. https://doi.org/10.1038/nn.2299
Miyawaki, Takahiro ; Ofengeim, Dimitry ; Noh, Kyung Min ; Latuszek-Barrantes, Adrianna ; Hemmings, Brian A. ; Follenzi, Antonia ; Zukin, R. Suzanne. / The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death. In: Nature Neuroscience. 2009 ; Vol. 12, No. 5. pp. 618-626.
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