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Gene profiling identifies commonalities in neuronal pathways in excitotoxicity: Evidence favouring cell cycle re-activation in concert with oxidative stress


Chen, MJ and Ng, JMJ and Peng, ZF and Manikandan, J and Yap, YW and Llanos, RM and Beart, PM and Cheung, NS, Gene profiling identifies commonalities in neuronal pathways in excitotoxicity: Evidence favouring cell cycle re-activation in concert with oxidative stress, Neurochemistry International, 62, (5) pp. 719-730. ISSN 0197-0186 (2013) [Refereed Article]

Copyright Statement

Copyright 2013 Elsevier Ltd.

DOI: doi:10.1016/j.neuint.2012.12.015


Excitotoxicity, induced by the aberrant rise in cytosolic Ca2+ level, is a major neuropathological process in numerous neurodegenerative disorders. It is triggered when extracellular glutamate (Glu) concentration reaches neuropathological levels resulting in dysregulation and hyper-activation of ionotropic glutamate receptor subtype (iGluRs). Even though all three members of the iGluRs, namely N-methyl-d-aspartate (NMDAR), α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR) and kainate (KAR) receptors are implicated in excitotoxicity, their individual contributions to downstream signaling transduction have not been explored. In this study, we report a comprehensive description of the recruitment of cellular processes in neurons upon iGluR activation during excitotoxicity through temporal (5 h, 15 h, and 24 h) global gene profiling of AMPA, KA, NMDA, and Glu excitotoxic models. DNA microarray analyses of mouse primary cortical neurons treated with these four pharmacological agonists are further validated via real-time PCR. Bi-model analyses against Glu model demonstrate that NMDARs and KARs play a more pivotal role in Glu-mediated excitotoxicity, with a higher degree of global gene profiling overlaps, as compared to that of AMPARs. Comparison of global transcriptomic profiles reveals aberrant calcium ion binding and homeostasis, organellar (lysosomal and endoplasmic reticulum) stress, oxidative stress, cell cycle re-entry and activation of cell death processes as the main pathways that are significantly modulated across all excitotoxicity models. Singular profile analyses demonstrate substantial transcriptional regulation of numerous cell cycle proteins. For the first time, we show that iGluR activation forms the basis of cell cycle re-activation, and together with oxidative stress fulfill the "two-hit" hypothesis that accelerates neurodegeneration. © 2012 Elsevier Ltd. All rights reserved.

Item Details

Item Type:Refereed Article
Keywords:Excitotoxicity, Ionotropic, L-Glutamate, Ischemic stroke, Cell cycle re-activation, Neuronal death, Microarray
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Cellular nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Chen, MJ (Ms Minghui Chen)
UTAS Author:Ng, JMJ (Mr Jeremy Ng)
ID Code:84485
Year Published:2013
Web of Science® Times Cited:11
Deposited By:Menzies Institute for Medical Research
Deposited On:2013-05-15
Last Modified:2014-04-17

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