额颞叶变性
聚ADP核糖聚合酶
化学
应力颗粒
免疫组织化学
细胞生物学
分子生物学
生物
癌症研究
聚合酶
蛋白质聚集
生物化学
失智症
酶
内科学
医学
免疫学
信使核糖核酸
痴呆
翻译(生物学)
基因
疾病
作者
Kunikazu Tanji,Fumiaki Mori,Fumiyuki Shirai,Takehiro Fukami,Hiroyuki Seimiya,Jun Utsumi,Akiyoshi Kakita,Koichi Wakabayashi
标识
DOI:10.1016/j.bbrc.2020.12.037
摘要
Abstract Transactive response DNA-binding protein of 43 kDa (TDP-43) abnormally forms aggregates in certain subtypes of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). The pathological forms of TDP-43 have reported to be associated with poly(ADP-ribose) (PAR), which regulates the properties of these aggregates. A recent study has indicated that tankyrase, a member of the PAR polymerase (PARP) family, regulates pathological TDP-43 formation under conditions of stress, and tankyrase inhibitors suppress TDP-43 aggregate formation and cytotoxicity. Since we reported the development of tankyrase inhibitors that are more specific than conventional inhibitors, in this study, we examined their effects on the formation of TDP-43 aggregates in cultured cells. Time-lapse imaging showed that TDP-43 aggregates appeared in the nucleus within 30 min of treatment with sodium arsenite. Several tankyrase inhibitors suppressed the formation of aggregates and decreased the levels of the tankyrase protein. Immunohistochemical studies demonstrated that tankyrase was localized to neuronal cytoplasmic inclusions in the spinal cords of patients with ALS. Moreover, the tankyrase protein levels were significantly higher in the brains of patients with FTLD than in the brains of control subjects. These findings suggest that the inhibition of tankyrase activity protects against TDP-43 toxicity. Tankyrase inhibitors may be a potential treatment to suppress the progression of TDP-43 proteinopathies.
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