In vitro evidence of propagation of superoxide dismutase-1 protein aggregation in canine degenerative myelopathy
In vitro evidence of propagation of superoxide dismutase-1 protein aggregation in canine degenerative myelopathy
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DOI：
10.1016/j.tvjl.2021.105710
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发表时间：
2021-06-27
影响因子：
2.2
通讯作者：
Kamishina, H.
中科院分区：
文献类型：
--
作者：
Tanaka, N.;Kimura, S.;Kamishina, H.
犬退行性脊髓病（DM）是一种进行性和致死性神经退行性疾病，与超氧化物歧化酶1（SOD 1）基因突变有关。错误折叠的蛋白聚集体在脊髓神经元和星形胶质细胞中的积累被认为是DM的重要病理过程;然而，蛋白聚集体形成的机制在很大程度上是未知的。在人类神经退行性疾病中，例如肌萎缩性侧索硬化症（ALS），已经证明了疾病相关蛋白质的细胞到细胞传播。因此，在本研究中，研究了突变SOD 1蛋白在DM中体外聚集形成特性的繁殖。该研究表明，通过与犬突变体SOD 1（E40 K SOD 1）共转染，由犬野生型SOD 1蛋白组成的聚集体增加，表明SOD 1聚集体的细胞内增殖。此外，聚集的重组SOD 1蛋白从细胞中释放，被其他细胞吸收，并诱导正常折叠的SOD 1蛋白的进一步聚集体形成。这些结果表明SOD 1聚集体的细胞间传播。在这项研究中提出的SOD 1聚集体的细胞到细胞传播的假设可能是DM病理学进行性的基础。
Canine degenerative myelopathy (DM) is a progressive and fatal neurodegenerative disorder that has been linked to mutations in the superoxide dismutase 1 (SOD1) gene. The accumulation of misfolded protein aggregates in spinal neurons and astrocytes is implicated as an important pathological process in DM; however, the mechanism of protein aggregate formation is largely unknown. In human neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), cell-to-cell propagation of disease-relevant proteins has been demonstrated. Therefore, in this study, propagation of aggregation-forming property of mutant SOD1 protein in DM in vitro was investigated. This study demonstrated that aggregates composed of canine wild type SOD1 protein were increased by cotransfection with canine mutant SOD1 (E40K SOD1), indicating intracellular propagation of SOD1 aggregates. Further, aggregated recombinant SOD1 proteins were released from the cells, taken up by other cells, and induced further aggregate formation of normally folded SOD1 proteins. These results suggest intercellular propagation of SOD1 aggregates. The hypothesis of cell-to-cell propagation of SOD1 aggregates proposed in this study may underly the progressive nature of DM pathology.