Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice
Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice
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DOI：
10.1111/j.1471-4159.2010.06753.x
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发表时间：
2010-07-01
影响因子：
4.7
通讯作者：
Marklund, Stefan L.
中科院分区：
文献类型：
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作者：
Bergemalm, Daniel;Forsberg, Karin;Marklund, Stefan L.
突变型超氧化物歧化酶-1 （SOD1）通过一种未知的细胞毒性机制导致肌萎缩性侧索硬化症（ALS）。ALS患者和携带人类SOD1 （hSOD1）突变的转基因小鼠模型的一个标志是脊髓腹角中存在hSOD1免疫反应性包涵体。hSOD1内含物可阻断基本细胞功能或通过隔离其他蛋白质引起毒性。四种不同转基因小鼠模型的包涵体经密度梯度超离心检测。夹杂物结构复杂，密度不均，易被洗涤剂破坏。聚集的hSOD1主要由缺乏天然稳定亚基内二硫键的亚基组成。一部分亚基形成hSOD1寡聚物或通过二硫键与其他蛋白质结合。用蛋白质组学技术对其蛋白质组成进行了分析。突变体hSOD1占了一半的蛋白质。另外还鉴定了10种蛋白质。其中2种是细胞质伴侣蛋白，4种是细胞骨架蛋白，4种是通常存在于内质网中的蛋白。在含有主要细胞质hSOD1的包涵体中存在内质网蛋白进一步支持了内质网应激参与ALS的观点。
P>Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from four different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intra-subunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, four were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.