An aggregate-prone mutant of human glyceraldehyde-3-phosphate dehydrogenase augments oxidative stress-induced cell death in SH-SY5Y cells

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• 作者：Hidemitsu Nakajima ; Wataru Amano ; Ayano Fukuhara ; Takeya Kubo ; Shouhei Misaki ; Yasu-Taka Azuma ; Takashi Inui ; Tadayoshi Takeuchi
• 关键词：GAPDH ; Oxidative stress ; Cell death ; Protein aggregation ; Mutation
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2009
• 出版时间：18 December 2009
• 年：2009
• 卷：390
• 期：3
• 页码：1066-1071
• 全文大小：568 K

文摘

Glycerladehyde-3-phosphate dehydrogenase (GAPDH), a classic glycolytic enzyme, also has a role in mediating cell death under oxidative stress. Our previous reports suggest that oxidative stress-induced GAPDH aggregate formation is, at least in part, a mechanism to account for the death signaling. Here we show that substitution of cysteine for serine-284 of human GAPDH (S284C-GAPDH) leads to aggregate-prone GAPDH, and that its expression in SH-SY5Y human neuroblastoma results in greater dopamine-induced cell death than expression of wild type-GAPDH. Treatment of purified recombinant S284C-GAPDH in vitro with the nitric oxide donor NOR3 led to greater aggregation than wild type-GAPDH. Several lines of structural analysis revealed that S284C-GAPDH was amyloidogenic. Overexpression of doxycycline-inducible S284C-GAPDH in SH-SY5Y cells accelerated dopamine treatment-induced death and increased formation of GAPDH aggregates, compared to cells expressing wild type-GAPDH. These results suggest that aggregate-prone mutations of GAPDH such as S284C-GAPDH may confer risk of oxidative stress-induced cell death.