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PTK2/FAK regulates UPS impairment via SQSTM1/p62 phosphorylation in TARDBP/TDP-43 proteinopathies.

Authors
  • Lee, Shinrye1
  • Jeon, Yu-Mi1
  • Cha, Sun Joo2
  • Kim, Seyeon1, 3
  • Kwon, Younghwi1, 3
  • Jo, Myungjin1
  • Jang, You-Na4
  • Lee, Seongsoo5
  • Kim, Jaekwang1
  • Kim, Sang Ryong6, 7
  • Lee, Kea Joo4
  • Lee, Sung Bae3
  • Kim, Kiyoung2, 8
  • Kim, Hyung-Jun1
  • 1 Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea. , (North Korea)
  • 2 Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan, South Korea. , (North Korea)
  • 3 Department of Brain & Cognitive Sciences, DGIST, Daegu, South Korea. , (North Korea)
  • 4 Neural circuits Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea. , (North Korea)
  • 5 Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju, South Korea. , (North Korea)
  • 6 School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Institute of Life Science & Biotechnology, Kyungpook National University, Daegu, South Korea. , (North Korea)
  • 7 Brain Science and Engineering Institute, Kyungpook National University, Daegu, South Korea. , (North Korea)
  • 8 Department of Medical Biotechnology, Soonchunhyang University, Asan, South Korea. , (North Korea)
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Nov 05, 2019
Pages
1–17
Identifiers
DOI: 10.1080/15548627.2019.1686729
PMID: 31690171
Source
Medline
Keywords
Language
English
License
Unknown

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.

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