Wenqiang Chen, Lonskaya Irina, Hebron Michaeline L, Ibrahim Zainab, Olszewski Rafal T, Neale Joseph H, Moussa Charbel E-H
Department of Traditional Chinese Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China Department of Neuroscience.
Department of Traditional Chinese Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
Hum Mol Genet. 2014 Sep 15;23(18):4960-9. doi: 10.1093/hmg/ddu211. Epub 2014 May 8.
The transactivation DNA-binding protein (TDP)-43 binds to thousands of mRNAs, but the functional outcomes of this binding remain largely unknown. TDP-43 binds to Park2 mRNA, which expresses the E3 ubiquitin ligase parkin. We previously demonstrated that parkin ubiquitinates TDP-43 and facilitates its translocation from the nucleus to the cytoplasm. Here we used brain penetrant tyrosine kinase inhibitors (TKIs), including nilotinib and bosutinib and showed that they reduce the level of nuclear TDP-43, abrogate its effects on neuronal loss, and reverse cognitive and motor decline. Nilotinib decreased soluble and insoluble TDP-43, while bosutinib did not affect the insoluble level. Parkin knockout mice exhibited high levels of endogenous TDP-43, while nilotinib and bosutinib did not alter TDP-43, underscoring an indispensable role for parkin in TDP-43 sub-cellular localization. These data demonstrate a novel functional relationship between parkin and TDP-43 and provide evidence that TKIs are potential therapeutic candidates for TDP-43 pathologies.
反式激活DNA结合蛋白（TDP）-43可与数千种mRNA结合，但其结合的功能后果仍 largely未知。TDP-43与表达E3泛素连接酶parkin的Park2 mRNA结合。我们之前证明parkin可使TDP-43泛素化，并促进其从细胞核转运至细胞质。在此，我们使用了包括尼洛替尼和博舒替尼在内的可穿透脑的酪氨酸激酶抑制剂（TKIs），结果表明它们可降低细胞核TDP-43的水平，消除其对神经元丢失的影响，并逆转认知和运动功能衰退。尼洛替尼可降低可溶性和不可溶性TDP-43的水平，而博舒替尼不影响不可溶性TDP-43的水平。Parkin基因敲除小鼠表现出高水平的内源性TDP-43，而尼洛替尼和博舒替尼并未改变TDP-43的水平，这突出了parkin在TDP-43亚细胞定位中的不可或缺的作用。这些数据证明了parkin与TDP-43之间存在一种新的功能关系，并提供了证据表明TKIs是TDP-43相关病变的潜在治疗候选药物。
