Jonsson P Andreas, Ernhill Karin, Andersen Peter M, Bergemalm Daniel, Brännström Thomas, Gredal Ole, Nilsson Peter, Marklund Stefan L
Clinical Chemistry, Department of Medical Biosciences, Umeå University Hospital, Sweden.
Brain. 2004 Jan;127(Pt 1):73-88. doi: 10.1093/brain/awh005. Epub 2003 Oct 8.
Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.
超氧化物歧化酶-1（SOD1）的突变形式通过一种未知的有害机制导致肌萎缩侧索硬化症（ALS）。利用一种针对G127insTGGG突变中新表位的抗体，首次在一名ALS患者的脊髓和大脑中对突变型SOD1进行了研究。其水平低于对照组中SOD1水平的0.5%。在相应的转基因小鼠中，突变型SOD1的含量也很低，尽管与其他组织相比，它在脊髓和大脑中有所富集。在小鼠中，错误折叠的突变型SOD1迅速聚集，20%以去污剂可溶的原聚集体形式处于稳态。从出生到死亡，错误折叠的SOD1和原聚集体形成了一种潜在的有害负担，可能会导致运动神经元损伤。在患者和患有终末期疾病的小鼠的脊髓腹角中，出现了抗去污剂聚集体以及运动神经元和星形胶质细胞中突变型SOD1的包涵体。这些包涵体和聚集体可能作为错误折叠的SOD1和原聚集体长期攻击的终末标志物。
