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
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 increase...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-03-01
|
| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fncel.2018.00079/full |
| _version_ | 1828795670918594560 |
|---|---|
| author | Liang Sun Liang Sun Kai Zhang Weiwei Zhai Haiying Li Haitao Shen Zhengquan Yu Gang Chen |
| author_facet | Liang Sun Liang Sun Kai Zhang Weiwei Zhai Haiying Li Haitao Shen Zhengquan Yu Gang Chen |
| author_sort | Liang Sun |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T04:08:18Z |
| format | Article |
| id | doaj.art-6caa270b25004259804732df761a5dd5 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-12T04:08:18Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-6caa270b25004259804732df761a5dd52022-12-22T00:38:42ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022018-03-011210.3389/fncel.2018.00079330337TAR DNA Binding Protein-43 Loss of Function Induced by Phosphorylation at S409/410 Blocks Autophagic Flux and Participates in Secondary Brain Injury After Intracerebral HemorrhageLiang Sun0Liang Sun1Kai Zhang2Weiwei Zhai3Haiying Li4Haitao Shen5Zhengquan Yu6Gang Chen7Department of Neurosurgery, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, ChinaThis 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.http://journal.frontiersin.org/article/10.3389/fncel.2018.00079/fullTDP-43nucleus lossmTORdynactin1autophagic fluxintracerebral hemorrhage |
| spellingShingle | Liang Sun Liang Sun Kai Zhang Weiwei Zhai Haiying Li Haitao Shen Zhengquan Yu Gang Chen 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 Frontiers in Cellular Neuroscience TDP-43 nucleus loss mTOR dynactin1 autophagic flux intracerebral hemorrhage |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | TDP-43 nucleus loss mTOR dynactin1 autophagic flux intracerebral hemorrhage |
| url | http://journal.frontiersin.org/article/10.3389/fncel.2018.00079/full |
| work_keys_str_mv | AT liangsun tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT liangsun tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT kaizhang tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT weiweizhai tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT haiyingli tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT haitaoshen tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT zhengquanyu tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage AT gangchen tardnabindingprotein43lossoffunctioninducedbyphosphorylationats409410blocksautophagicfluxandparticipatesinsecondarybraininjuryafterintracerebralhemorrhage |