Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, Yokohama, 223-8522, Japan.
Department of Neurology, Matsumoto Medical Center, Matsumoto, 399-0021, Japan.
Mol Neurodegener. 2019 Nov 19;14(1):42. doi: 10.1186/s13024-019-0341-5.
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.
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.
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.
Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.
一部分家族性肌萎缩侧索硬化症（ALS）是由编码铜/锌超氧化物歧化酶（SOD1）的基因突变引起的。突变的 SOD1 蛋白易发生错误折叠并异常堆积在脊髓中，这在 ALS 中受影响最严重。然而，野生型 SOD1 的错误折叠是否参与了没有 SOD1 突变的更为常见的散发性 ALS（sALS）病例，这仍然存在很大争议。
使用免疫沉淀测定法和使用专门识别错误折叠 SOD1 的抗体的三明治 ELISA，检测包括 sALS 以及其他几种神经退行性疾病和非神经退行性疾病在内的患者的脑脊液（CSF）。
我们发现，在本研究中检查的所有 sALS 病例的 CSF 中，野生型 SOD1 发生错误折叠。在帕金森病和进行性核上性麻痹的 CSF 中也检测到了错误折叠的 SOD1，尽管其含量比 sALS 中的少。此外，含有错误折叠 SOD1 的 CSF 样品对运动神经元样 NSC-34 细胞具有显著的毒性，而用免疫沉淀去除错误折叠的野生型 SOD1 可减轻其毒性。
综上所述，我们提出，无论 SOD1 是否突变，CSF 中野生型 SOD1 的错误折叠是 ALS 病例的一个共同病理过程。
