BACKGROUND A subset of familial forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1). Mutant SOD1 proteins are susceptible to misfolding and abnormally accumulated in spinal cord, which is most severely affected in ALS. It, however, remains quite controversial whether misfolding of wild-type SOD1 is involved in more prevalent sporadic ALS (sALS) cases without SOD1 mutations. METHODS Cerebrospinal fluid (CSF) from patients including sALS as well as several other neurodegenerative diseases and non-neurodegenerative diseases was examined with an immunoprecipitation assay and a sandwich ELISA using antibodies specifically recognizing misfolded SOD1. RESULTS We found that wild-type SOD1 was misfolded in CSF from all sALS cases examined in this study. The misfolded SOD1 was also detected in CSF from a subset of Parkinson's disease and progressive supranuclear palsy, albeit with smaller amounts than those in sALS. Furthermore, the CSF samples containing the misfolded SOD1 exhibited significant toxicity toward motor neuron-like NSC-34 cells, which was ameliorated by removal of the misfolded wild-type SOD1 with immunoprecipitation. CONCLUSIONS Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.

中文翻译：

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野生型铜/锌超氧化物歧化酶在散发性肌萎缩性侧索硬化的脑脊髓液中错折叠。

背景肌萎缩性侧索硬化症（ALS）的家族型子集是由编码Cu / Zn超氧化物歧化酶（SOD1）的基因突变引起的。突变的SOD1蛋白易于错误折叠并在脊髓中异常积聚，这在ALS中受到最严重的影响。但是，野生型SOD1的错误折叠是否涉及更普遍的无SOD1突变的散发ALS（sALS）案例，仍然存在争议。方法采用免疫沉淀测定法和夹心ELISA法，使用特异性识别错误折叠的SOD1的抗体，对包括sALS以及其他几种神经退行性疾病和非神经退行性疾病的患者的脑脊液（CSF）进行了检查。结果我们发现，在本研究中检查的所有sALS病例中，野生型SOD1在CSF中均错折叠。还从一部分帕金森氏病和进行性核上性麻痹的脑脊液中检测到错误折叠的SOD1，尽管其数量少于sALS。此外，含有错误折叠的SOD1的CSF样品对运动神经元样NSC-34细胞表现出显着的毒性，通过免疫沉淀去除错误折叠的野生型SOD1可以改善这种毒性。结论综上所述，我们认为无论SOD1突变如何，脑脊液中野生型SOD1的错误折叠都是ALS患者的常见病理过程。通过用免疫沉淀去除错误折叠的野生型SOD1可以改善这种情况。结论综上所述，我们认为无论SOD1突变如何，脑脊液中野生型SOD1的错误折叠都是ALS患者的常见病理过程。通过用免疫沉淀去除错误折叠的野生型SOD1可以改善这种情况。结论综上所述，我们认为无论SOD1突变如何，脑脊液中野生型SOD1的错误折叠都是ALS患者的常见病理过程。