Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.
Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pone.0010627
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发表时间：
2010-05-13
期刊：
影响因子：
3.7
通讯作者：
Jackson GS
中科院分区：
文献类型：
--
作者：
Chia R;Tattum MH;Jones S;Collinge J;Fisher EM;Jackson GS
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特异性地影响运动神经元并导致进行性且最终致命的功能丧失，通常在诊断后3至5年内导致死亡。这种疾病开始于一个薄弱的焦点，如一个肢体，并似乎蔓延到身体的其他部位。已知超氧化物歧化酶1（SOD 1）的突变会引起疾病，并且通常认为它们不是通过酶活性的丧失而是通过获得一些未知的毒性功能而导致病理学。虽然不同的突变导致不同的趋势SOD1聚集，我们认为异常蛋白质共享一个共同的错误折叠途径，导致淀粉样纤维的形成。在这里，我们表明，超氧化物歧化酶1的错误折叠导致与播种活动，这可以加速形成新的纤维在自催化级联淀粉样纤维的形成。时间限制事件是在快速线性聚合导致类似于其他蛋白质错误折叠病症的淀粉样原纤维之前成核以形成稳定的蛋白质“种子”。这种现象并不局限于原纤维的重组蛋白，因为在这里，我们表明，第一次，脊髓匀浆获得过表达突变型人超氧化物歧化酶1（TgSOD1G93A小鼠）的转基因小鼠模型也包含淀粉样蛋白种子，加速形成新的原纤维在野生型和突变型SOD 1蛋白在体外。这些发现为ALS疾病机制提供了新的见解，特别是可以解释病理在整个神经系统中传播的机制。这种疾病传播的模型与其他蛋白质错误折叠疾病（如朊病毒疾病）类似，也表明可能设计用于抑制原纤维繁殖并因此可能抑制疾病进展的治疗方法的测定。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal centre of weakness, such as one limb, and appears to spread to other parts of the body. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s). Although different mutations lead to varying tendencies of SOD1 to aggregate, we suggest abnormal proteins share a common misfolding pathway that leads to the formation of amyloid fibrils. Here we demonstrate that misfolding of superoxide dismutase 1 leads to the formation of amyloid fibrils associated with seeding activity, which can accelerate the formation of new fibrils in an autocatalytic cascade. The time limiting event is nucleation to form a stable protein “seed” before a rapid linear polymerisation results in amyloid fibrils analogous to other protein misfolding disorders. This phenomenon was not confined to fibrils of recombinant protein as here we show, for the first time, that spinal cord homogenates obtained from a transgenic mouse model that overexpresses mutant human superoxide dismutase 1 (the TgSOD1G93A mouse) also contain amyloid seeds that accelerate the formation of new fibrils in both wildtype and mutant SOD1 protein in vitro. These findings provide new insights into ALS disease mechanism and in particular a mechanism that could account for the spread of pathology throughout the nervous system. This model of disease spread, which has analogies to other protein misfolding disorders such as prion disease, also suggests it may be possible to design assays for therapeutics that can inhibit fibril propagation and hence, possibly, disease progression.
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影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
DOI：
10.1073/pnas.0704307104
发表时间：
2007-07-03
影响因子：
11.1
作者：
Banci, Lucia;Bertini, Ivano;Whitelegge, Julian P.
通讯作者：
Whitelegge, Julian P.
影响因子：
4.8
作者：
Furukawa, Y;O'Halloran, TV
通讯作者：
O'Halloran, TV
影响因子：
4.8
作者：
Furukawa, Yoshiaki;Kaneko, Kumi;Nukina, Nobuyuki
通讯作者：
Nukina, Nobuyuki
影响因子：
5.3
作者：
Baglioni, Serena;Casamenti, Fiorella;Stefani, Massimo
通讯作者：
Stefani, Massimo