Liu Hsueh-Ning, Sanelli Teresa, Horne Patrick, Pioro Erik P, Strong Michael J, Rogaeva Ekaterina, Bilbao Juan, Zinman Lorne, Robertson Janice
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Ann Neurol. 2009 Jul;66(1):75-80. doi: 10.1002/ana.21704.
In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1) mutations (fALS1), SOD1 toxicity has been linked to its propensity to misfold and aggregate. It has recently been proposed that misfolded SOD1 may be causative of all types of ALS, including sporadic cases (sALS). In the present study, we have used a specific antibody to test for the presence of monomer/misfolded SOD1 in sALS.
Sections from lumbar spinal cords of 5 fALS1 cases, 13 sALS cases, and 1 non-SOD1 fALS case were labeled immunocytochemically using SOD1-exposed-dimer-interface (SEDI) antibody, which we have previously validated as being specific for pathological monomer/misfolded forms of SOD1.
Monomer/misfolded SOD1 was detected with SEDI antibody in all 5 of the fALS1 cases, localizing predominantly to hyaline conglomerate inclusions, a specific pathological feature of fALS1. In contrast, monomer/misfolded SOD1 was not detected in any of the 13 sALS cases or in the non-SOD1 fALS cases. These results were confirmed by immunoprecipitation.
Although SEDI antibody does not necessarily label all misfolded forms of SOD1, these findings show a distinct difference between fALS1 and sALS, and do not support that monomer/misfolded SOD1 is a common disease entity linking all types of ALS. This is important to our understanding of ALS disease pathogenesis and to considerations of the applicability of using therapeutics that target misfolded SOD1 to non-SOD1-related cases. Ann Neurol 2009;66:75-80.
在携带超氧化物歧化酶（SOD1）突变的家族性肌萎缩侧索硬化症（fALS）（fALS1）中，SOD1毒性与其错误折叠和聚集的倾向有关。最近有人提出，错误折叠的SOD1可能是所有类型肌萎缩侧索硬化症的病因，包括散发性病例（sALS）。在本研究中，我们使用一种特异性抗体来检测sALS中单体/错误折叠的SOD1的存在。
对5例fALS1病例、13例sALS病例和1例非SOD1 fALS病例的腰段脊髓切片进行免疫细胞化学标记，使用SOD1暴露二聚体界面（SEDI）抗体，我们之前已验证该抗体对SOD1的病理性单体/错误折叠形式具有特异性。
在所有5例fALS1病例中均用SEDI抗体检测到单体/错误折叠的SOD1，主要定位于透明聚集体包涵体，这是fALS1的一种特定病理特征。相比之下，在13例sALS病例或非SOD1 fALS病例中均未检测到单体/错误折叠的SOD1。这些结果通过免疫沉淀得到证实。
虽然SEDI抗体不一定能标记SOD1的所有错误折叠形式，但这些发现显示了fALS1和sALS之间的明显差异，并不支持单体/错误折叠的SOD1是连接所有类型肌萎缩侧索硬化症的常见疾病实体。这对于我们理解肌萎缩侧索硬化症的发病机制以及考虑将针对错误折叠SOD1的治疗方法应用于非SOD1相关病例的适用性具有重要意义。《神经病学纪事》2009年；66：75 - 80。
