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The Journal of Neuroscience, February 11, 2004, 24(6):1280-1287; doi:10.1523/JNEUROSCI.4082-03.2004

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Neurobiology of Disease
Ectopic Expression of the Catalytic Subunit of Telomerase Protects against Brain Injury Resulting from Ischemia and NMDA-Induced Neurotoxicity

Hyo Jung Kang,^1 * Yoon Sik Choi,^2 * Seung-Beom Hong,^2 * Kee-Won Kim,³ Ran-Sook Woo,³ Seok Joon Won,¹ Eun Ju Kim,² Hee Kyung Jeon,² So-Young Jo,² Tae Kook Kim,⁴ Robert Bachoo,⁵ Ian J. Reynolds,⁶ Byoung Joo Gwag,¹ and Han-Woong Lee²

¹Departments of Neuroscience and Pharmacology, Ajou University School of Medicine, Suwon 442-749, Korea, ²Department of Molecular Cell Biology, Samsung Biomedical Research Center, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea, ³Department of Pharmacology and Institute for Medical Sciences, Chonbuk University Medical School, San 2-20 Keumam-dong, Chonju 561-180, Korea, ⁴Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea, ⁵Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, and ⁶Department of Pharmacology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261

The catalytic subunit of telomerase reverse transcriptase (TERT) protects dividing cells from replicative senescence in vitro. Here, we show that expression of TERT mRNA is induced in the ipsilateral cortical neurons after occlusion of the middle cerebral artery in adult mice. Transgenic mice that overexpress TERT showed significant resistance to ischemic brain injury. Among excitotoxicity, oxidative stress, and apoptosis comprising of routes of ischemic neuronal death, NMDA receptor-mediated excitotoxicity was reduced in forebrain cell cultures overexpressing TERT. NMDA-induced accumulation of cytosolic free Ca²⁺ ([Ca²⁺]_c) was reduced in forebrain neurons from TERT transgenic mice, which was attributable to the rapid flow of [Ca²⁺]_c into the mitochondria from the cytosol without change in Ca²⁺ influx and efflux through the plasma membrane. The present study provides evidence that TERT is inducible in postmitotic neurons after ischemic brain injury and prevents NMDA neurotoxicity through shift of the cytosolic free Ca²⁺ into the mitochondria, and thus plays a protective role in ameliorating ischemic neuronal cell death.

Key words: catalytic subunit of telomerase; ischemia; excitotoxicity; NMDA; calcium; mitochondria

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Received Sep 4, 2003; revised October 22, 2003; accepted October 22, 2003.

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