TRANSGENIC MICE EXPRESSING AN ALTERED MURINE SUPEROXIDE-DISMUTASE GENE PROVIDE AN ANIMAL-MODEL OF AMYOTROPHIC-LATERAL-SCLEROSIS
TRANSGENIC MICE EXPRESSING AN ALTERED MURINE SUPEROXIDE-DISMUTASE GENE PROVIDE AN ANIMAL-MODEL OF AMYOTROPHIC-LATERAL-SCLEROSIS
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DOI：
10.1073/pnas.92.3.689
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发表时间：
1995-01-31
影响因子：
11.1
通讯作者：
GORDON, JW
中科院分区：
文献类型：
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作者：
RIPPS, ME;HUNTLEY, GW;GORDON, JW
肌萎缩侧索硬化症是一种进行性神经退行性疾病，主要涉及运动神经元。具有家族性常染色体显性形式的疾病的个体的子集具有铜/锌超氧化物歧化酶（Cu/Zn SOD，SOD-1）基因的突变，该基因编码在氧自由基清除中起关键作用的普遍表达的酶。这一观察结果表明，改变或减少SOD-1活性可能在神经退行性过程中发挥作用。为了进一步探索这种可能性，我们在小鼠SOD-1基因中引入了一个突变，该突变对应于家族性肌萎缩侧索硬化症中人类基因中发现的变化之一。通过引入突变产生的转基因编码序列中存在独特的限制性内切酶位点，鉴定转基因小鼠中该小鼠基因的整合和表达。我们在这里报告，这种改变的基因在转基因小鼠的中枢神经系统的高表达与年龄相关的运动功能的快速进行性下降，伴随着脊髓，脑干和新皮质内的运动神经元的退行性变化。这些结果表明，改变SOD活性和运动神经元变性之间的因果关系。此外，生物化学研究表明转基因小鼠组织中总SOD活性水平正常，结果表明神经退行性疾病不是由活性降低引起的，因此，代表了显性“功能获得”突变。
Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder primarily involving motoneurons. A subset of individuals with familial autosomal dominant forms of the disease have mutations of the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free radical scavenging. This observation suggests that altered or reduced SOD-1 activity may play a role in the neurodegenerative process. To explore this possibility further, we have introduced a mutation into the mouse SOD-1 gene that corresponds to one of the changes found in the human gene in familial amyotrophic lateral sclerosis. Integration and expression of this mouse gene in transgenic mice was identified by the presence of a unique restriction enzyme site in the transgene coding sequence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. These findings indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate normal levels of total SOD activity in transgenic mouse tissues, results that indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant ''gain of function'' mutation.