Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis
Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis
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DOI：
10.1038/nn1603
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发表时间：
2006
影响因子：
25
通讯作者：
M. Urushitani;A. Sik;T. Sakurai;N. Nukina;R. Takahashi;J. Julien
中科院分区：
文献类型：
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作者：
M. Urushitani;A. Sik;T. Sakurai;N. Nukina;R. Takahashi;J. Julien
在这里，我们报告了嗜铬颗粒蛋白，神经分泌囊泡的成分，与与肌萎缩侧索硬化症(ALS)相关的突变形式的超氧化物歧化酶(SOD1)相互作用，但不与野生型SOD1相互作用。酵母菌双杂交筛选和免疫共沉淀试验证实了这种相互作用，无论是共表达嗜铬颗粒蛋白的Neuro2a细胞裂解物还是ALS小鼠脊髓裂解物。共聚焦显微镜和免疫电子显微镜显示突变型SOD1与嗜铬颗粒蛋白在ALS小鼠脊髓中部分共存。在免疫隔离的反式高尔基体网络和微生物体制剂中也发现了突变的SOD1，这表明它可以被分泌。事实上，我们报告的证据表明，嗜铬颗粒蛋白可能作为伴侣样蛋白促进SOD1突变体的分泌。根据这些结果，以及我们发现细胞外突变体SOD1可以触发小胶质细胞增殖和神经元死亡，我们提出了一个新的基于分泌型SOD1突变体毒性的ALS致病模型。
Here we report that chromogranins, components of neurosecretory vesicles, interact with mutant forms of superoxide dismutase (SOD1) that are linked to amyotrophic lateral sclerosis (ALS), but not with wild-type SOD1. This interaction was confirmed by yeast two-hybrid screen and by co-immunoprecipitation assays using either lysates from Neuro2a cells coexpressing chromogranins and SOD1 mutants or lysates from spinal cord of ALS mice. Confocal and immunoelectron microscopy revealed a partial colocalization of mutant SOD1 with chromogranins in spinal cord of ALS mice. Mutant SOD1 was also found in immuno-isolated trans-Golgi network and in microsome preparations, suggesting that it can be secreted. Indeed we report evidence that chromogranins may act as chaperone-like proteins to promote secretion of SOD1 mutants. From these results, and our finding that extracellular mutant SOD1 can trigger microgliosis and neuronal death, we propose a new ALS pathogenic model based on the toxicity of secreted SOD1 mutants.