Elucidation of the aggregation mechanism of the mutant superoxide dismutase1 (SOD1) in patients with familial amyotrophic lateral sclerosis with SOD1 gene mutation and their animal models

阐明突变型超氧化物歧化酶1（SOD1）在家族性肌萎缩侧索硬化症患者及其动物模型中的聚集机制

• 批准号: 13680821
• 负责人: KATO Shinsuke
• 金额: $ 2.3万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680821/
• 关键词: Familial amyotrophic lateral sclerosis; Superoxide dismutase 1(SOD1); Granule-coated fibril; Aggregation toxicity; Maillard reaction; Cupper chaperone for SOD; Hepatocyte growth factor; Redox system; superoxide dismutase 1; c-Met; ペルオキシレドキシン; グ

We have elucidated the aggregation mechanism of the mutant superoxide dismutase1 (SOD1) in patients with familial amyotrophic lateral sclerosis with SOD1 gene mutation and their animal models. This mutant SOD1 aggregation leads to their motor neuron death. Granule-coated fibrils are ultrastructural morphological hallmarks of this mutant SOD1 aggregation toxicity. Maillard reaction [advanced glycation endproduct (AGE) formation] contributes to the granule-coated fibril formation : the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e.,granule-coated fibril formation), which leads to the neuronal cell death. The increase of these granule-coated fibrils means intracellular inclusion formation. When the inclusions have been growing, co-aggregation or sequestration into the inclusions (i.e.,granule-coated fibrils themselves) has been observed for normal cytosolic constitutive proteins, copper chaperone for SOD (chaperone specifically carried copper to SOD1), hepatocyte growth factor (neurotrophic factor), and proxiredoxin/glutathione peroxidase directly regulating a redox system. These are also endogenous mechanisms that accelerate neuronal death.

我们已经阐明了具有SOD1基因突变及其动物模型的家族性肌萎缩性侧性硬化症患者的突变体超氧化物歧化酶1（SOD1）的聚集机制。这种突变的SOD1聚集导致其运动神经元死亡。颗粒状的原纤维是该突变SOD1聚集毒性的超微结构形态标志。 Maillard反应[高级糖基化终产物（年龄）形成]有助于颗粒涂层的原纤维形成：年龄改性的SOD1（可能是年龄改性的突变SOD1）的形成是导致聚集的机制之一（即颗粒涂层的纤维形成），导致了死亡的细胞。这些涂有颗粒的原纤维的增加意味着细胞内夹杂物的形成。当夹杂物增长时，已经观察到对正常的细胞质组成蛋白，SOD的铜伴侣蛋白（伴侣辅助辅助铜（SOD1），肝细胞生长因子（Hepatocyte croverte crovise）（hepatocyte croltirotianciest）的正常细胞质组成蛋白，铜伴侣蛋白（伴侣），并固定在夹杂物中（即颗粒涂层的原纤维本身）（即颗粒涂层的原纤维）。调节氧化还原系统。这些也是加速神经元死亡的内源性机制。

项目成果

加藤信介: "運動ニューロンのグリケーション"Brain Medical. (印刷中).

Shinsuke Kato：“运动神经元的糖化”脑医学（正在出版）。

Kato S et al. (分担執筆): "Molecular Mechanism and Therapeutics of Amyotrophic Lateral Sclerosis"ELSEVIER SCIENCE B.V.. 382 (2001)

Kato S 等人（撰稿人）：“肌萎缩侧索硬化症的分子机制和治疗”ELSEVIER SCIENCE B.V.. 382 (2001)

Kato S., et al.: "Monoclonal antibody to stage-specific fetal brain 68-kDa glycoprotein (FGP68) revealed increased FGP68 expression in human primary brain tumors."Acta Neuropathologica. 104/1. 57-66 (2002)

Kato S. 等人：“针对阶段特异性胎儿脑 68-kDa 糖蛋白 (FGP68) 的单克隆抗体显示人类原发性脑肿瘤中 FGP68 表达增加。”《神经病理学报》。

Yamashita S., et al.: "Bcl-2 expression using retrograde transport of adenoviral vectors inhibits cytochrome c-release and caspase-1 activation in motor neurons of mutant superoxide dismutase 1 (G93A) transgenic mice."Neurosci Lett. 350/1. 17-20 (2003)

Yamashita S. 等人：“使用腺病毒载体逆行转运的 Bcl-2 表达抑制突变超氧化物歧化酶 1 (G93A) 转基因小鼠运动神经元中的细胞色素 c 释放和 caspase-1 激活。”Neurosci Lett。

Yamashita S. et al.: "Bcl-2 expression using retrograde transport of adenoviral vectors inhibits cytochrome c-release and caspase-1 activation in motor neurons of mutant superoxide dismutase 1 (G93A) transgonic mice."Neurosci Lett. 350・1. 17-20 (2003)

Yamashita S. 等人：“使用腺病毒载体逆行转运的 Bcl-2 表达抑制突变超氧化物歧化酶 1 (G93A) 转基因小鼠运动神经元中的细胞色素 c 释放和 caspase-1 激活。”Neurosci Lett。 17-20 (2003)