Spinocerebellar ataxia type 35 (SCA35)-associated transglutaminase 6 mutants sensitize cells to apoptosis |
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| Authors: | Wen-Juan Guan Jun-Ling Wang Yu-Tao Liu Yan-Tao Ma Ying Zhou Hong Jiang Lu Shen Ji-Feng Guo Kun Xia Jia-Da Li Bei-Sha Tang |
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| Institution: | 1. Hemostasis Laboratory, Rabin Medical Center, Beilinson Hospital, Petach Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;2. Thrombosis and Hemostasis Unit, Rabin Medical Center, Beilinson Hospital, Petach Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;3. Clinical Research Center, Haemostasis, Thrombosis and Vascular Biology Research Group of the Hungarian Academy of Sciences, University of Debrecen, Medical & Health Science Center, Debrecen, Hungary;4. Thrombosis and Hemostasis Unit, Sheba Medical Center, Tel Hashomer, Israel;1. Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China;2. Department of Clinical Epidemiology & Biostatistics, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China;3. Department of Epidemiology & Health Statistics, School of Public Health, School of Medicine, Zhejiang University, Hangzhou 310058, China;4. Anhui Provience Children’s Hospital, Hefei 230022, China |
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| Abstract: | 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 γ-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. |
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