Neuronal pentraxin 1 induction in hypoxic-ischemic neuronal death is regulated via a glycogen synthase kinase-3α/β dependent mechanism.

Mark McIntosh,'s picture
PubMed URL: 
http://www.ncbi.nlm.nih.gov/pubmed/21130869
Author: 
Hossain MA
Author List: 
Russell JC
Kishimoto K
O'Driscoll C
Hossain MA
Journal: 
Cell Signal
PubMed ID: 
21130869
Pagination: 
673-82
Volume: 
23
Issue: 
4
Abstract: 
Intracellular signaling pathways that regulate the production of lethal proteins in central neurons are not fully characterized. Previously, we reported induction of a novel neuronal protein neuronal pentraxin 1 (NP1) in neonatal brain injury following hypoxia-ischemia (HI); however, how NP1 is induced in hypoxic-ischemic neuronal death remains elusive. Here, we have elucidated the intracellular signaling regulation of NP1 induction in neuronal death. Primary cortical neurons showed a hypoxic-ischemia time-dependent increase in cell death and that NP1 induction preceded the actual neuronal death. NP1 gene silencing by NP1-specific siRNA significantly reduced neuronal death. The specificity of NP1 induction in neuronal death was further confirmed by using NP1 (-/-) null primary cortical neurons. Declines in phospho-Akt (i.e. deactivation) were observed concurrent with decreased phosphorylation of its downstream substrate GSK-3α/β (at Ser21/Ser9) (i.e. activation) and increased GSK-3α and GSK-3β kinase activities, which occurred prior to NP1 induction. Expression of a dominant-negative inhibitor of Akt (Akt-kd) blocked phosphorylation of GSK-3α/β and subsequently enhanced NP1 induction. Whereas, overexpression of constitutively activated Akt (Akt-myr) or wild-type Akt (wtAkt) increased GSK-α/β phosphorylation and attenuated NP1 induction. Transfection of neurons with GSK-3α siRNA completely blocked NP1 induction and cell death. Similarly, overexpression of the GSK-3β inhibitor Frat1 or the kinase mutant GSK-3βKM, but not the wild-type GSK-3βWT, blocked NP1 induction and rescued neurons from death. Our findings clearly implicate both GSK-3α- and GSK-3β-dependent mechanism of NP1 induction and point to a novel mechanism in the regulation of hypoxic-ischemic neuronal death.
Published Date: 
April, 2011

Bradley L. Schlaggar, M.D., Ph.D., Named President and CEO of Kennedy Krieger Institute

We’re thrilled to welcome Bradley L. Schlaggar, M.D., Ph.D., to the Kennedy Krieger family as our next President and CEO.

Learn more.

Appointments & Referrals

FIND A SPECIALIST

Publications

Read inspiring stories, news and updates about the Institute's patient care, research, special education, professional training, and community programs.

 

Resource Finder

 

A free resource that provides access to information and support for individuals and families living with developmental disabilities.