Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation.
Transglutaminase inhibition protects against oxidative stress-induced neuronal death downstream of pathological ERK activation.
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DOI：
10.1523/jneurosci.3353-11.2012
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发表时间：
2012-05-09
期刊：
影响因子：
--
通讯作者：
Ratan RR
中科院分区：
文献类型：
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作者：
Basso M;Berlin J;Xia L;Sleiman SF;Ko B;Haskew-Layton R;Kim E;Antonyak MA;Cerione RA;Iismaa SE;Willis D;Cho S;Ratan RR
转谷氨酰胺酶2(TG2)的分子缺失已被证明可以改善包括中风、亨廷顿病和帕金森病在内的一系列神经系统疾病的功能和存活率。然而，这些交联酶或多胺化酶广泛参与神经元死亡的统一方案尚未提出。出乎意料的是，我们发现，除了TG2，TG1基因的表达水平在体内卒中后或体外氧化应激后显著诱导。强迫表达TG1或TG2蛋白足以诱导体外培养的褐家鼠皮质神经元死亡。因此，单独的TG2分子缺失不足以保护小鼠肌肉神经元免受氧化死亡的影响。相比之下，结构不同的抑制剂在同时抑制TG1和TG2的浓度下可以起到神经保护作用。这些小分子抑制氧化应激诱导的神经元转胺活性的增加；当在死亡刺激开始很久之后加入时，它们也保护病理性ERK激活的下游神经元。综上所述，这些研究表明，多种TG亚型，而不仅仅是TG2，参与了氧化应激诱导的细胞死亡信号；并且TG的异构体非选择性抑制剂在对抗神经系统疾病中的氧化死亡将是最有效的。
Molecular deletion of transglutaminase 2 (TG2) has been shown to improve function and survival in a host of neurological conditions including stroke, Huntington’s disease, and Parkinson’s disease. However, unifying schemes by which these crosslinking or polyaminating enzymes participate broadly in neuronal death have yet to be presented. Unexpectedly, we found that in addition to TG2, TG1 gene expression level is significantly induced following stroke in vivo or due to oxidative stress in vitro. Forced expression of TG1 or TG2 proteins is sufficient to induce neuronal death in Rattus novergicus cortical neurons in vitro. Accordingly, molecular deletion of TG2 alone is insufficient to protect Mus musculus neurons from oxidative death. By contrast, structurally diverse inhibitors used at concentrations that inhibit TG1 and TG2 simultaneously are neuroprotective. These small molecules inhibit increases in neuronal transamidating activity induced by oxidative stress; they also protect neurons downstream of pathological ERK activation when added well after the onset of the death stimulus. Together, these studies suggest that multiple TG isoforms, not only TG2, participate in oxidative stress-induced cell death signaling; and that isoform non-selective inhibitors of TG will be most efficacious in combating oxidative death in neurological disorders.