The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease
The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease
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DOI：
10.1073/pnas.93.11.5472
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发表时间：
1996-05-28
影响因子：
11.1
通讯作者：
DalCanto, MC
中科院分区：
文献类型：
--
作者：
Mourelatos, Z;Gonatas, NK;DalCanto, MC
在某些家族性肌萎缩侧索硬化症(ALS)家族成员中发现了编码铜、锌超氧化物歧化酶的SOD1基因的显性突变。为了更好地了解SOD1突变在家族性ALS发病机制中的作用，我们开发了表达家族性ALS中发现的一种突变的转基因小鼠。这些动物的临床和病理特征与人类ALS非常相似。这些动物早期观察到的变化是由于内质网扩张和线粒体空泡变性导致的轴突内和树突内的空泡。我们曾报道散发性ALS患者脊髓运动神经元高尔基体支离破碎和萎缩。在这项研究中，我们发现SOD1突变转基因小鼠的脊髓运动神经元表现出高尔基体的损害，与在散发性ALS人类中发现的相同。在这些小鼠中，碎裂的高尔基体的小脑池比正常细胞器中的小池短，粗面内质网中与高尔基体相关的小泡和邻近的小池减少。此外，高尔基体的碎裂发生在症状前的早期阶段，通常先于液泡变化的发展。过度表达野生型人类超氧化物歧化酶的转基因小鼠是正常的。在家族性肌萎缩侧索硬化症中，运动神经元高尔基体的早期损害可能会对功能产生不利影响，因为新合成的、用于轴浆快速运输的蛋白质会通过高尔基体。
Dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase have been found in members of certain families with familial amyotrophic lateral sclerosis (ALS). To better understand the contribution of SOD1 mutations in the pathogenesis of familial ALS, we developed transgenic mice expressing one of the mutations found in familial ALS. These animals display clinical and pathological features closely resembling human ALS. Early changes observed in these animals were intra-axonal and dendritic vacuoles due to dilatation of the endoplasmic reticulum and vacuolar degeneration of mitochondria. We have reported that the Golgi apparatus of spinal cord motor neurons in patients with sporadic ALS is fragmented and atrophic. In this study we show that spinal cord motor neurons of transgenic mice for an SOD1 mutation display a lesion of the Golgi apparatus identical to that found in humans with sporadic ALS. In these mice, the stacks of the cisternae of the fragmented Golgi apparatus are shorter than in the normal organelle, and there is a reduction in Golgi-associated vesicles and adjacent cisternae of the rough endoplasmic reticulum. Furthermore, the fragmentation of the Golgi apparatus occurs in an early, presymptomatic stage and usually precedes the development of the vacuolar changes. Transgenic mice overexpressing the wild-type human superoxide dismutase are normal. In familial ALS, an early lesion of the Golgi apparatus of motor neurons may have adverse functional effects, because newly synthesized proteins destined for fast axoplasmic transport pass through the Golgi apparatus.