臺灣博碩士論文加值系統

肌肉萎縮性側索硬化症 (Amyotrophic Lateral Sclerosis, ALS)，是一種進行性運動神經元萎縮或肌肉萎縮症。ALS可分為兩型：百分之八十五到九十ALS屬於偶發性 (Sporadic, SALS)，其致病原因，仍不清楚，可能與環境因素有關。另外百分之十到十五屬於遺傳性(Familial, FALS)。於FALS病例中，有近百分之二十歸因於銅鋅超氧化物岐化酵素 (Cu,Zn-SOD)基因突變所造成。使其Cu,Zn-SOD蛋白質的金屬結合能力受到改變，降低Cu,Zn-SOD蛋白質之活性 。本研究假設重金屬鎘在SOD蛋白組合時，干擾同族及性質相近過渡元素的銅鋅，造成活性下降，用於解釋環境因素產生的SALS。
首先，從人類肝臟組織cDNA中，利用RT-PCR之技術，選殖出人類的SOD1基因。以大腸桿菌在0.5 mM的銅及鋅濃度下過量表現最高酵素活性的Cu,Zn-SOD，測定大腸桿菌對鎘之最大耐受度為500 nM。於SDS-PAGE與西方墨點法分析可見23 kDa之Cu,Zn-SOD之過量表現。氯化鎘濃度的提高，Cu,Zn-SOD 之活性隨之下降。並利用石墨爐式原子吸收光譜儀，分析純化之Cu,Zn-SOD中所含金屬銅和鋅的含量變化，結果顯示，隨著氯化鎘濃度之提高，每毫克之 Cu,Zn-SOD所測得之鎘的含量亦隨之增高；相反的，鋅的含量卻隨之減少，但銅的含量則無變化。因此鎘金屬影響Cu,Zn-SOD蛋白質之活性降低，是經由影響鋅在Cu,Zn-SOD的結合力。利用圓振二向色性分析二級結構變化，發現鎘會造成α-helix和β-sheet結構的增加。
鎘影響Cu,Zn-SOD蛋白質之活性降低，除了少數鎘金屬的取代外，造成鋅離子的大量流失，其機制為鎘會誘導金屬硫蛋白大量的表現結合鋅離子，造成結合至Cu,Zn-SOD蛋白質中的鋅離子相對的流失。
本研究結果推測環境污染物重金屬鎘，可能藉由此一途徑，在 Cu,Zn-SOD 表現時影響鋅離子的結合，對於探討偶發性ALS之致病機制，提供一個新的方向。

Of Amyotrophic Lateral Sclerosis (ALS) , a progressive neurodegenerative disorder cases, 10% are familial and 90% are sporadic. The mutations found in the Cu,Zn-SOD (SOD1) are the causes of 20% of familial ALS. Most mutations cause the decrease of the SOD enzyme activity and some of them are due to the loss of zinc affinity or alteration of the zinc binding site.
Zinc and cadmium constitute group IIB of the periodic table of elements and are uniformly divalent. They share certain common biological responses. In order to investigate the possible causes of heavy metal interactions, we have constructed, expressed, and purified human Cu,Zn-SOD in E. coli with equal amounts of copper and zinc but different concentrations of cadmium in LB broth. First, SDS-PAGE and western blot analysis illustrated a 23kDa monomer. Second, the more cadmium added, the lower enzyme activities remained. Third, by atomic absorption spectrophotometer, we found that the more cadmium added, the more cadmium atoms and the less zinc atoms detected in purified Cu,Zn-SOD.
The results of observation and estimation of the purified Cu,Zn-SOD protein structure from native gel and circular dichroism indicate that the structure of apo-SOD, without any metals, is much different from Cu,Zn-SOD and Cu,Zn-SOD with 500 nM cadmium. Besides, secondary structure of Cu,Zn-SOD with 500 nM cadmium is much close to apo-SOD.
On the other hand, we have confirmed that cadmium is a strong inducer of metallothionein as previous studies reported. These results indicated that cadmium might effect zinc contents of Cu,Zn-SOD owing to its strong induction of metallothioneins which also bind zinc. Therefore, cadmium might play a role in sporadic ALS. These findings may offer some directions to study pathogenic mechanism.

章節目錄
中文摘要 I
英文摘要 III
章節目錄 V
圖表目錄 VI
縮寫表 VII
前言 1
實驗材料與方法 14
結果 31
討論 39
表、圖 43
參考文獻 58

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