Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, Shinrye | - |
dc.contributor.author | Jeon, Yu-Mi | - |
dc.contributor.author | Cha, Sun Joo | - |
dc.contributor.author | Kim, Seyeon | - |
dc.contributor.author | Kwon, Younghwi | - |
dc.contributor.author | Jo, Myungjin | - |
dc.contributor.author | Jang, You-Na | - |
dc.contributor.author | Lee, Seongsoo | - |
dc.contributor.author | Kim, Jaekwang | - |
dc.contributor.author | Kim, Sang Ryong | - |
dc.contributor.author | Lee, Kea Joo | - |
dc.contributor.author | Lee, Sung Bae | - |
dc.contributor.author | Kim, Kiyoung | - |
dc.contributor.author | Kim, Hyung-Jun | - |
dc.date.accessioned | 2019-12-12T08:37:59Z | - |
dc.date.available | 2019-12-12T08:37:59Z | - |
dc.date.created | 2019-11-27 | - |
dc.date.issued | 2020-08 | - |
dc.identifier.issn | 1554-8627 | - |
dc.identifier.uri | http://hdl.handle.net/20.500.11750/10933 | - |
dc.description.abstract | TARDBP/TDP-43 (TAR DNA binding protein) proteinopathies are a common feature in a variety of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer disease (AD). However, the molecular mechanisms underlying TARDBP-induced neurotoxicity are largely unknown. In this study, we demonstrated that TARDBP proteinopathies induce impairment in the ubiquitin proteasome system (UPS), as evidenced by an accumulation of ubiquitinated proteins and a reduction in proteasome activity in neuronal cells. Through kinase inhibitor screening, we identified PTK2/FAK (PTK2 protein tyrosine kinase 2) as a suppressor of neurotoxicity induced by UPS impairment. Importantly, PTK2 inhibition significantly reduced ubiquitin aggregates and attenuated TARDBP-induced cytotoxicity in a Drosophila model of TARDBP proteinopathies. We further identified that phosphorylation of SQSTM1/p62 (sequestosome 1) at S403 (p-SQSTM1 [S403]), a key component in the autophagic degradation of poly-ubiquitinated proteins, is increased upon TARDBP overexpression and is dependent on the activation of PTK2 in neuronal cells. Moreover, expressing a non-phosphorylated form of SQSTM1 (SQSTM1S403A) significantly repressed the accumulation of insoluble poly-ubiquitinated proteins and neurotoxicity induced by TARDBP overexpression in neuronal cells. In addition, TBK1 (TANK binding kinase 1), a kinase that phosphorylates S403 of SQSTM1, was found to be involved in the PTK2-mediated phosphorylation of SQSTM1. Taken together, our data suggest that the PTK2-TBK1-SQSTM1 axis plays a critical role in the pathogenesis of TARDBP by regulating neurotoxicity induced by UPS impairment. Therefore, targeting the PTK2-TBK1-SQSTM1 axis may represent a novel therapeutic intervention for neurodegenerative diseases with TARDBP proteinopathies.Abbreviations: ALP: macroautophagy/autophagy lysosomal pathway; ALS: amyotrophic lateral sclerosis; ATXN2: ataxin 2; BafA1: bafilomycin A1; cCASP3: cleaved caspase 3; CSNK2: casein kinase 2; FTLD: frontotemporal lobar degeneration; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; OPTN: optineurin; PTK2/FAK: PTK2 protein tyrosine kinase 2; SQSTM1/p62: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system. © 2019 Informa UK Limited, trading as Taylor & Francis Group. | - |
dc.language | English | - |
dc.publisher | Taylor and Francis | - |
dc.title | PTK2/FAK regulates UPS impairment via SQSTM1/p62 phosphorylation in TARDBP/TDP-43 proteinopathies | - |
dc.type | Article | - |
dc.identifier.doi | 10.1080/15548627.2019.1686729 | - |
dc.identifier.wosid | 000494612400001 | - |
dc.identifier.scopusid | 2-s2.0-85074810951 | - |
dc.identifier.bibliographicCitation | Autophagy, v.16, no.8, pp.1396 - 1412 | - |
dc.description.isOpenAccess | FALSE | - |
dc.subject.keywordAuthor | Amyotrophic lateral sclerosis | - |
dc.subject.keywordAuthor | PTK2 | - |
dc.subject.keywordAuthor | FAK | - |
dc.subject.keywordAuthor | SQSTM1 | - |
dc.subject.keywordAuthor | p62 | - |
dc.subject.keywordAuthor | TARDBP | - |
dc.subject.keywordAuthor | TDP-43 | - |
dc.subject.keywordAuthor | ubiquitin-proteasome system | - |
dc.subject.keywordPlus | AMYOTROPHIC-LATERAL-SCLEROSIS | - |
dc.subject.keywordPlus | FOCAL ADHESION KINASE | - |
dc.subject.keywordPlus | UBIQUITIN-PROTEASOME SYSTEM | - |
dc.subject.keywordPlus | FRONTOTEMPORAL LOBAR DEGENERATION | - |
dc.subject.keywordPlus | SELECTIVE AUTOPHAGY | - |
dc.subject.keywordPlus | CELL-DEATH | - |
dc.subject.keywordPlus | TDP-43 | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | DISEASE | - |
dc.subject.keywordPlus | PATHOGENESIS | - |
dc.citation.endPage | 1412 | - |
dc.citation.number | 8 | - |
dc.citation.startPage | 1396 | - |
dc.citation.title | Autophagy | - |
dc.citation.volume | 16 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Cell Biology | - |
dc.relation.journalWebOfScienceCategory | Cell Biology | - |
dc.type.docType | Article | - |
There are no files associated with this item.