Tucholski Janusz, Roth Kevin A, Johnson Gail V W
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294, USA.
J Neurochem. 2006 Apr;97(2):582-94. doi: 10.1111/j.1471-4159.2006.03780.x. Epub 2006 Mar 15.
Tissue transglutaminase (tTG) post-translationally modifies proteins in a calcium-dependent manner by incorporation of polyamines, deamination or crosslinking. Moreover, tTG can also bind and hydrolyze GTP. tTG is the major transglutaminase in the mammalian nervous system, localizing predominantly in neurons. Although tTG has been clearly demonstrated to be elevated in neurodegenerative diseases and in response to acute CNS injury, its role in these pathogenic processes remains unclear. Transgenic mice that overexpress human tTG (htTG) primarily in CNS neurons were generated to explore the role of tTG in the nervous system and its contribution to neuropathological processes. tTG transgenic mice were phenotypically normal and were born with the expected Mendelian frequency. However, when challenged systemically with kainic acid, tTG transgenic mice, in comparison to wild-type (WT) mice, developed more extensive hippocampal neuronal damage. This was evidenced by a decreased number of healthy neurons, and increased terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) labeling as an indicator of neuronal cell death in the kainic acid-treated transgenic mice. Moreover, the duration and severity of seizures developed by htTG transgenics in response to kainic acid administration were significantly more pronounced than those observed in WT mice. These data indicate for the first time that tTG may play an active role in excitatory amino acid-induced neuronal cell death, which has been postulated to be an important component of acute CNS injury and chronic CNS neurodegenerative conditions.
组织转谷氨酰胺酶（tTG）通过掺入多胺、脱氨或交联以钙依赖的方式对蛋白质进行翻译后修饰。此外，tTG还能结合并水解GTP。tTG是哺乳动物神经系统中的主要转谷氨酰胺酶，主要定位于神经元。尽管tTG在神经退行性疾病和急性中枢神经系统损伤反应中明显升高，但其在这些致病过程中的作用仍不清楚。为了探究tTG在神经系统中的作用及其对神经病理过程的影响，构建了主要在中枢神经系统神经元中过表达人tTG（htTG）的转基因小鼠。tTG转基因小鼠表型正常，出生频率符合预期孟德尔频率。然而，当用海藻酸进行全身攻击时，与野生型（WT）小鼠相比，tTG转基因小鼠出现了更广泛的海马神经元损伤。这表现为健康神经元数量减少，以及在海藻酸处理的转基因小鼠中，作为神经元细胞死亡指标的末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）标记增加。此外，htTG转基因小鼠对海藻酸给药产生的癫痫发作持续时间和严重程度明显比WT小鼠更显著。这些数据首次表明，tTG可能在兴奋性氨基酸诱导的神经元细胞死亡中发挥积极作用，而兴奋性氨基酸诱导的神经元细胞死亡被认为是急性中枢神经系统损伤和慢性中枢神经系统神经退行性疾病的重要组成部分。
