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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00079

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

Liang Sun1, 2, Kai Zhang2, Weiwei Zhai2, Haiying Li2,  Haitao Shen2, Zhengquan Yu2 and  Gang Chen2*
  • 1Huai'an First People's Hospital, China
  • 2First Affiliated Hospital of Soochow University, China

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, and calcineurin 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.

Keywords: TDP-43, Nucleus loss, mTOR, Dynaction1, Autophagic Flux, intracerebral hemorrhage, Calcineurin.

Received: 14 Nov 2017; Accepted: 07 Mar 2018.

Edited by:

Changlian Zhu, Third Affiliated Hospital of Zhengzhou University, China

Reviewed by:

Chin Hsu, Kaohsiung Medical University, Taiwan
Jing Gao, Jiangsu University, China  

Copyright: © 2018 Sun, Zhang, Zhai, Li, Shen, Yu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Gang Chen, First Affiliated Hospital of Soochow University, Suzhou, China,