Document Details
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Document Type |
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Article In Journal |
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Document Title |
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Gene profiling identifies commonalities in neuronal pathways in excitotoxicity: evidence favouring cell cycle re-activation in concert with oxidative stress. Gene profiling identifies commonalities in neuronal pathways in excitotoxicity: evidence favouring cell cycle re-activation in concert with oxidative stress. |
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Document Language |
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English |
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Abstract |
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Excitotoxicity, induced by the aberrant rise in cytosolic Ca(2+) 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 (5h, 15h, and 24h) 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. |
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ISSN |
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0197-0186 |
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Journal Name |
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Neurochemistry international |
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Volume |
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62 |
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Issue Number |
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5 |
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Publishing Year |
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1434 AH
2013 AD |
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Article Type |
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Article |
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Added Date |
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Monday, April 11, 2016 |
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Researchers
| Minghui Jessica Chen | Chen, Minghui Jessica | Investigator | | |
| Jian Ming Jeremy Ng | Ng, Jian Ming Jeremy | Researcher | | |
| Zhao Feng Peng | Peng, Zhao Feng | Researcher | | |
| Jayapal Manikandan | Manikandan, Jayapal | Researcher | | |
| Yann Wan Yap | Yap, Yann Wan | Researcher | | |
| Roxana M Llanos | Llanos, Roxana M | Researcher | | |
| Philip M Beart | Beart, Philip M | Researcher | | |
| Nam Sang Cheung | Cheung, Nam Sang | Researcher | | |
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