Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds
Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds
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DOI：
10.1093/hmg/8.8.1451
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发表时间：
1999-08-01
影响因子：
3.5
通讯作者：
Borchelt, DR
中科院分区：
文献类型：
--
作者：
Ratovitski, T;Corson, LB;Borchelt, DR
超氧化物歧化酶1(SOD1)多肽的突变会引起一种形式的家族性肌萎缩侧索硬化症(FALS)，在不同的家族中，包含不同的突变，对于给定的突变，病程往往是相似的。例如，在第四位(A4V)遗传用缬氨酸替代丙氨酸的患者在出现症状后平均预期寿命为1.5年，而在第46位(H46R)用精氨酸替代组氨酸的患者在发病后平均预期寿命为18年。在这里，我们检测了SOD1多肽的九种不同FALS变体的一些生化和生物物理性质，包括酶活性(它间接与酶对铜的亲和力有关)、多肽半衰期、对蛋白降解的抵抗力和溶解性，以努力确定这些酶的特定属性是否与临床进展相关，我们发现，尽管所有测试的突变体似乎都是可溶的，但不同的突变体在活性、多肽半衰期和对蛋白分解的抵抗力方面表现出显著的差异，然而，这些变量没有以与临床进展相关的方式分层。我们的结论是，不同类型的SOD1连锁FAL患者的预期寿命不同的基础可能是这些突变酶的一种未知属性所致。
Mutations in superoxide dismutase 1 (SOD1) polypeptides cause a form of familial amyotrophic lateral sclerosis (FALS), In different kindreds, harboring different mutations, the duration of illness tends to be similar for a given mutation. For example, patients inheriting a substitution of valine for alanine at position four (A4V) average a 1.5 year life expectancy after the onset of symptoms, whereas patients harboring a substitution of arginine for histidine at position 46 (H46R) average an 18 year life expectancy after disease onset. Here, we examine a number of biochemical and biophysical properties of nine different FALS variants of SOD1 polypeptides, including enzymatic activity (which relates indirectly to the affinity of the enzyme for copper), polypeptide half-life, resistance to proteolytic degradation and solubility, in an effort to determine whether a specific property of these enzymes correlates with clinical progression, We find that although all the mutants tested appear to be soluble, the different mutants show a remarkable degree of variation with respect to activity, polypeptide half-life and resistance to proteolysis, However, these variables do not stratify in a manner that correlates with clinical progression. We conclude that the basis for the different life expectancies of patients in different kindreds of sod1-linked FALS may result from an as yet unidentified property of these mutant enzymes.