Sakudo Akikazu, Lee Deug-chan, Saeki Keiichi, Nakamura Yuko, Inoue Keiichi, Matsumoto Yoshitsugu, Itohara Shigeyoshi, Onodera Takashi
Department of Molecular Immunology, School of Agricultural and Life Sciences, University of Tokyo, Japan.
Biochem Biophys Res Commun. 2003 Aug 29;308(3):660-7. doi: 10.1016/s0006-291x(03)01459-1.
Previous studies have reported a neuroprotective role for cellular prion protein (PrP(C)) against apoptosis induced by serum deprivation in an immortalized prion protein gene (Prnp)-deficient neuronal cell line, but the mechanisms remain unclear. In this study, to investigate the mechanisms by which PrP(C) prevents apoptosis, the authors compared apoptosis of Prnp(-/-) cells with that of Prnp(-/-) cells expressing the wild-type PrP(C) or PrP(C) lacking N-terminal octapeptide repeat region under serum-free conditions. Re-introduction of Prnp rescued cells from apoptosis, upregulated superoxide dismutase (SOD) activity, enhanced superoxide anion elimination, and inhibited caspase-3/9 activation. On the other hand, N-terminally truncated PrP(C) enhanced apoptosis accompanied by potentiation of superoxide production and caspase-3/9 activation due to inhibition of SOD. These results suggest that PrP(C) protects Prnp(-/-) cells from apoptosis via superoxide- and caspase-3/9-dependent pathways by upregulating SOD activity. Furthermore, the octapeptide repeat region of PrP(C) plays an essential role in regulating apoptosis and SOD activity.
以往研究报道，细胞朊蛋白（PrP(C)）在永生化朊蛋白基因（Prnp）缺陷的神经元细胞系中，对血清剥夺诱导的细胞凋亡具有神经保护作用，但其机制尚不清楚。在本研究中，为了探究PrP(C)预防细胞凋亡的机制，作者在无血清条件下，比较了Prnp(-/-)细胞与表达野生型PrP(C)或缺乏N端八肽重复区域的PrP(C)的Prnp(-/-)细胞的凋亡情况。重新引入Prnp可使细胞免于凋亡，上调超氧化物歧化酶（SOD）活性，增强超氧阴离子清除，并抑制caspase-3/9激活。另一方面，由于SOD受到抑制，N端截短的PrP(C)会增强细胞凋亡，同时伴有超氧产生增加和caspase-3/9激活。这些结果表明，PrP(C)通过上调SOD活性，经超氧化物和caspase-3/9依赖的途径保护Prnp(-/-)细胞免于凋亡。此外，PrP(C)的八肽重复区域在调节细胞凋亡和SOD活性中起重要作用。
