TAR DNA Binding Protein-43 Loss of Function Induced by Phosphorylation at S409/410 Blocks Autophagic Flux and Participates in Secondary Brain Injury After Intracerebral Hemorrhage.
TAR DNA Binding Protein-43 Loss of Function Induced by Phosphorylation at S409/410 Blocks Autophagic Flux and Participates in Secondary Brain Injury After Intracerebral Hemorrhage.
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TAR DNA 结合蛋白-43 由 S409/410 磷酸化引起的功能丧失会阻碍自噬流并参与脑出血后的继发性脑损伤
DOI：
10.3389/fncel.2018.00079
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发表时间：
2018
影响因子：
5.3
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Sun L;Zhang K;Zhai W;Li H;Shen H;Yu Z;Chen G
本研究旨在确定TAR DNA结合蛋白 - 43（TDP - 43）在脑出血（ICH）诱导的继发性脑损伤（SBI）中的作用及其潜在机制。脑出血后，体内和体外实验均显示细胞核中TDP - 43的表达显著降低，而细胞质中的表达增加，这表明在脑出血后的继发性脑损伤过程中TDP - 43从细胞核转移至细胞质。此外，TDP - 43的S409/410位点突变可抑制其磷酸化，减轻核丢失，并消除皮质下神经元凋亡的增加。抑制TDP - 43磷酸化可减轻脑出血诱导的哺乳动物雷帕霉素靶蛋白（mTOR）活性和动力蛋白激活蛋白1（dynactin1）表达的下调，这可能缓解自噬体 - 溶酶体融合受阻以及脑出血诱导的自噬体和溶酶体生物发生的增加。然而，敲低TDP - 43会加重脑出血诱导的继发性脑损伤。此外，TDP - 43可被钙调神经磷酸酶（CN）去磷酸化，并且氧合血红蛋白（OxyHb）处理可增加CN活性。总之，本研究表明，S409/410位点磷酸化导致的TDP - 43功能缺失可能通过抑制mTOR活性和dynactin1表达来阻断自噬体 - 溶酶体融合，并诱导微管相关蛋白1轻链3 - II（LC3II）和p62水平升高。这种机制可能在脑出血诱导的继发性脑损伤中起重要作用，并且TDP - 43可能是一个潜在的治疗靶点。
This study aimed to determine the role of TAR DNA binding protein-43 (TDP-43) in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and its underlying mechanisms. After ICH, expression of TDP-43 in the nucleus was significantly decreased, and its expression in the cytoplasm increased both in vivo and in vitro, which indicates that TDP-43 translocates from the nucleus to the cytoplasm during SBI after ICH. In addition, mutations at S409/410 of TDP-43 could inhibit its phosphorylation, attenuate nuclear loss, and abolish the increase in neuronal apoptosis in the subcortex. Inhibition of TDP-43 phosphorylation attenuated ICH-induced downregulation of mTOR activity and dynactin1 expression, which may relieve blocking of autophagosome-lysosome fusion and the increase of autophagosomal and lysosomal biogenesis induced by ICH. However, knockdown of TDP-43 could worsen ICH-induced SBI. Furthermore, TDP-43 could be dephosphorylated by calcineurin (CN), and CN activity was increased by OxyHb treatment. In conclusion, this study demonstrated that TDP-43 loss-of-function by phosphorylation at S409/410 may block autophagosome-lysosome fusion and induce elevation of LC3II and p62 levels by inhibiting the activity of mTOR and expression of dynactin1. This mechanism may play an important role in ICH-induced SBI, and TDP-43 may be a potential therapeutic target.
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影响因子：
7.1
作者：
Fatima M;Tan R;Halliday GM;Kril JJ
通讯作者：
Kril JJ
影响因子：
7.1
作者：
Sullivan PM;Zhou X;Robins AM;Paushter DH;Kim D;Smolka MB;Hu F
通讯作者：
Hu F
影响因子：
4.8
作者：
Suzuki, Hiroaki;Lee, Kikyo;Matsuoka, Masaaki
通讯作者：
Matsuoka, Masaaki
影响因子：
4.4
作者：
Wu, Zehan;Zou, Xiang;Zhao, Fan
通讯作者：
Zhao, Fan
DOI：
10.1073/pnas.1608432113
发表时间：
2016-11-22
影响因子：
11.1
作者：
Le, Nhat T. T.;Chang, Lydia;Monteiro, Mervyn J.
通讯作者：
Monteiro, Mervyn J.