The endogenous inhibitor of Akt, CTMP, is critical to ischemia-induced neuronal death (Nat Neurosci, 2009, 12:618-626)

報告日期: 2009/12/04
報告時間: 16:00/16:50
報告學生: 劉威廷
講評老師: 莊季瑛
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/981204-2.pdf

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

 

Nature Neuroscience 12, 618-626, 2009  

 

Speaker: Wei-Ting Liu (劉威廷)

Commentator: Jih-Ing Chuang, Ph.D. (莊季瑛 老師)

Time: 16:00-16:50, Dec 4, 2009

Place: room 602

 

Abstract

    Transient global or forebrain ischemia arising as a consequence of cardiac arrest or surgery of the heart and brain leads to delayed neuronal death of CA1 hippocampal neurons and impaired cognition. Ischemic preconditioning also called ischemic tolerance is a well-established phenomenon that a sub-threshold ischemic insult acts certain cellular pathways that can help to reduce damage and protect CA1 neurons against a subsequent severe ischemic challenge. Several studies support ischemic preconditioning promotes phosphorylation of Akt which is important in mediating neuronal survival of a wide range of neuronal cell type and phosphorylation/inactivation of downstream targets that have been implicated in mechanisms of cell death. However, paradoxically, ischemic insults elicit a marked, albeit transient, increase of phosphorylated Akt (p-Akt) in neurons that are destined to die. CTMP (carboxyl-terminal modulator protein) is an endogenous inhibitor of p-Akt that binds and extinguishes Akt activity. It is still unclear that the molecular and cellular mechanism underlying ischemia-induced neuronal death. The authors found that ischemia markedly promoted Akt phosphorylation, but not kinase activity or phosphorylation of downstream targets such as GSK-3b and FOXO3A in selectively vulnerable hippocampal CA1 neurons. It was observed that CTMP expression was be induced by ischemia and mirrored the loss of Akt activity in postichemic neurons. Direct delivery of CTMP microRNA to the hippocampal CA1 by a lentiviral system before ischemia rescued hippocampal neurons through the restore of Akt activity and phosphorylation. Thus, these findings indicated that CTMP was essential to ischemia-induced neuronal death and identified CTMP as a therapeutic target for the intervention in the neurodegeneration and cognitive deficits associated with global ischemia.

 

References

1.    Lo, E.H, et al. Mechanisms, challenges and opportunities in storke. Nat. Rev. Neurosci. 4, 399-415, 2003.

2.    Maira, S.M, et al Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294, 374–380, 2001.

3.    Gidday, J.M, Cerebral preconditioning and ischaemic tolerance. Nat. Rev. Neurosci. 7, 437–448, 2006.