• Biochem. Biophys. Res. Commun. · Dec 2009

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

    • Hidemitsu Nakajima, Wataru Amano, Ayano Fukuhara, Takeya Kubo, Shouhei Misaki, Yasu-Taka Azuma, Takashi Inui, and Tadayoshi Takeuchi.
    • Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Izumisano, Osaka 5988531, Japan. hnakajima@vet.osakafu-u.ac.jp
    • Biochem. Biophys. Res. Commun. 2009 Dec 18; 390 (3): 1066-71.

    AbstractGlycerladehyde-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.

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