Yamanaka Koji
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University.
Rinsho Shinkeigaku. 2014;54(12):1148-50. doi: 10.5692/clinicalneurol.54.1148.
Dominant mutations in the TDP-43 gene are causative for familial ALS, however, the relationship between mutant protein biochemical phenotypes and disease course and their significance to disease pathomechanism are unclarified. We found that longer half-lives of mutant proteins correlated with accelerated disease onset. Increased stability of TDP-43 protein was also observed in ALS/FTLD linked mutations in RNA recognition motif of TDP-43. Based on our findings, we established a cell model in which chronic stabilization of wild-type TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent sarkosyl, TDP-43 properties that have been observed in the lesions of sporadic ALS. Moreover, these cells expressing stabilized TDP-43 showed proteasomal impairment and dysregulation of their own mRNA levels. These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis.
TDP - 43基因的显性突变是家族性肌萎缩侧索硬化症（ALS）的病因，然而，突变蛋白的生化表型与疾病进程之间的关系及其对疾病发病机制的意义尚不清楚。我们发现，突变蛋白的较长半衰期与疾病发作加速相关。在TDP - 43的RNA识别基序中与ALS/额颞叶痴呆（FTLD）相关的突变中，也观察到TDP - 43蛋白稳定性增加。基于我们的发现，我们建立了一个细胞模型，其中野生型TDP - 43蛋白的慢性稳定引发了细胞毒性，并重现了致病性蛋白裂解以及对去污剂 Sarkosyl 的不溶性，这些是散发性ALS病变中观察到的TDP - 43特性。此外，这些表达稳定化TDP - 43的细胞显示出蛋白酶体损伤及其自身mRNA水平的失调。这些结果表明，突变型或野生型TDP - 43蛋白的慢性稳定性增加通过异常的蛋白质稳态导致毒性增加。
