Identification of Three Mutations in the Cu, Zn-Superoxide Dismutase(Cu,Zn-SOD) Gene with Familial Amyotrophic Lateral Sclerosis

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Taipei Medical University Institutional Repository > 醫學院 > 醫學系 > 生物化學暨細胞分子生物學科 > 期刊論文 > Item 987654321/13795

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题名:	Identification of Three Mutations in the Cu, Zn-Superoxide Dismutase(Cu,Zn-SOD) Gene with Familial Amyotrophic Lateral Sclerosis
作者:	周志銘;陳建志;施純明 Chou CM;;Huang CJ;;Shih CM;;Chen YP;;Liu TP;;Chen CT
贡献者:	醫學系生化學科
日期:	2005
上传时间:	2009-10-28 13:56:00 (UTC+8)
摘要:	The most frequent genetic causes of amyotrophic lateral sclerosis (ALS) determined so far are mutations occurring in the gene coding for copper/zinc superoxide dismutase (Cu,Zn-SOD). The mechanism may involve the formation of hydroxyl radicals or malfunctioning of the SOD protein. Wild-type SOD1 was constructed into a transcription-translation expression vector to examine the SOD1 production in vitro. Wild-type SOD1 was highly expressed in Escherichia coli. Active SOD1 was expressed in a metal-dependent manner. To investigate the possible roles of genetic causes of ALS, a human Cu,Zn-SOD gene was fused with a gene fragment encoding the nine amino acid transactivator of transcription (Tat) protein transduction domain (RKKRRQRRR) of human immunodeficiency virus type 1 in a bacterial expression vector to produce a genetic in-frame Tat-SOD1 fusion protein. The expressed and purified Tat-SOD1 fusion proteins in E. coli can enter PC12 neural cells to observe the cellular consequences. Denatured Tat-SOD1 was successfully transduced into PC12 cells and retained its activity via protein refolding. Three point mutations, E21K, D90V, and D101G, were cloned by site-directed mutagenesis and showed lower SOD1 activity. In undifferentiated PC12 cells, wild-type Tat-SOD1 could prevent DNA fragmentation due to superoxide anion attacks generated by 35 mM paraquat, whereas mutant Tat-D101G enhanced cell death. Our results demonstrate that exogenous human Cu,Zn-SOD fused with Tat protein can be directly transduced into cells, and the delivered enzymatically active Tat-SOD exhibits a cellular protective function against oxidative stress.
關聯:	Ann N Y Acad. Sci.(1042):303-313.
数据类型:	article
显示于类别:	[生物化學暨細胞分子生物學科] 期刊論文

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