Novel tankyrase inhibitors suppress TDP-43 aggregate formation
Novel tankyrase inhibitors suppress TDP-43 aggregate formation
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新型端锚聚合酶抑制剂抑制 TDP-43 聚集体形成
DOI：
10.1016/j.bbrc.2020.12.037
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发表时间：
2021
影响因子：
3.1
通讯作者：
Wakabayashi Koichi
中科院分区：
文献类型：
--
作者：
Tanji Kunikazu;Mori Fumiaki;Shirai Fumiyuki;Fukami Takehiro;Seimiya Hiroyuki;Utsumi Jun;Kakita Akiyoshi;Wakabayashi Koichi
在额颞叶变性（FTLD）和肌萎缩侧索硬化（ALS）的某些亚型中，43 kDa的反式反应DNA结合蛋白（TDP-43）异常形成聚集体。已报道TDP-43的病理形式与调节这些聚集体的性质的聚（ADP-核糖）（PAR）相关。最近的研究表明，端锚聚合酶，PAR聚合酶（PARP）家族的成员，调节应激条件下病理TDP-43的形成，端锚聚合酶抑制剂抑制TDP-43聚集体的形成和细胞毒性。由于我们报道了比常规抑制剂更特异的端锚聚合酶抑制剂的开发，因此在本研究中，我们检查了它们对培养细胞中TDP-43聚集体形成的影响。延时成像显示，TDP-43聚集体出现在细胞核内的亚砷酸钠治疗30分钟。几种端锚聚合酶抑制剂抑制聚集体的形成并降低端锚聚合酶蛋白的水平。免疫组织化学研究表明，端锚聚合酶定位于ALS患者脊髓神经元胞质内含物。此外，端锚聚合酶蛋白水平在FTLD患者的大脑中显著高于对照受试者的大脑。这些发现表明端锚聚合酶活性的抑制保护免受TDP-43毒性。端锚聚合酶抑制剂可能是抑制TDP-43蛋白病进展的潜在治疗方法。
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.