Spinocerebellar ataxia type 35 (SCA35)-associated transglutaminase 6 mutants sensitize cells to apoptosis
Spinocerebellar ataxia type 35 (SCA35)-associated transglutaminase 6 mutants sensitize cells to apoptosis
复制标题
脊髓小脑共济失调 35 型 (SCA35) 相关转谷氨酰胺酶 6 突变体使细胞对细胞凋亡敏感
DOI：
10.1016/j.bbrc.2012.11.069
复制
发表时间：
2013-01-11
影响因子：
3.1
通讯作者：
Tang, Bei-Sha
中科院分区：
文献类型：
--
作者：
Guan, Wen-Juan;Wang, Jun-Ling;Tang, Bei-Sha
脊髓小脑性共济失调35型(SCA35)是一种常染色体显性遗传性神经退行性疾病。在我们先前的研究中，利用外显子序列和连锁分析，两个转谷氨酰胺酶6(TGM6)基因的错义突变被鉴定为引起SCA35的原因。TGM6编码转谷氨酰胺酶6(TG6)，转谷氨酰胺酶家族中的一个成员，催化蛋白质或多肽结合的谷氨酰胺的游离胺基团和伽马-甲酰胺基团之间形成共价键。然而，TG6在SCA35中的确切作用仍不清楚。在本研究中，我们分析了TG6(D327G，L517W)两个错义突变的亚细胞分布、表达和体外活性，发现这两个突变都表现出转谷氨酰胺酶活性和稳定性的降低。此外，过表达TG6突变体通过增加半胱氨酸天冬氨酸氨基转移酶的活性，使细胞对星形孢子素诱导的细胞凋亡敏感。我们认为这些突变体的促凋亡作用可能是SCA35发病的基础。(C)2012 Elsevier Inc.保留所有权利。
Spinocerebellar ataxia type 35 (SCA35) is an autosomal dominant neurodegenerative disorder. In our previous study, using exome sequencing and linkage analysis, two missense mutations of the transglutaminase 6 (TGM6) gene were identified as causative for SCA35. TGM6 encodes transglutaminase 6 (TG6), a member of the transglutaminase family of enzymes that catalyze the formation of a covalent bond between a free amine group and the gamma-carboxamide group of protein- or peptide-bound glutamine. However, the precise role of TG6 in contributing to SCA35 remains unclear. In this study, we analyzed the subcellular distribution, expression and in vitro activity of two missense mutations of TG6 (D327G, L517W) and found that both mutants exhibited decreased transglutaminase activity and stability. Furthermore, overexpressing the TG6 mutants sensitized cells to staurosporine-induced apoptosis by increasing the activity of caspases. We propose that the pro-apoptotic role of these mutants might underlie the pathogenesis of SCA35. (C) 2012 Elsevier Inc. All rights reserved.