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PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

Shinrye Lee, Yu-Mi Jeon, Seyeon Kim, Younghwi Kwon, Myungjin Jo, You-Na Jang, Seongsoo Lee, Jaekwang Kim, Sang Ryong Kim, Kea Joo Lee, Sung Bae Lee, Kiyoung Kim, Hyung-Jun Kim
doi: https://doi.org/10.1101/355446
Shinrye Lee
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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Yu-Mi Jeon
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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Seyeon Kim
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
2Department of Brain & Cognitive Sciences, DGIST, Daegu, South Korea, 42988
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Younghwi Kwon
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
2Department of Brain & Cognitive Sciences, DGIST, Daegu, South Korea, 42988
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Myungjin Jo
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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You-Na Jang
3Department of Structure and Function of Neural Network, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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Seongsoo Lee
4Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju, South Korea, 61186
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Jaekwang Kim
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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Sang Ryong Kim
5School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Institute of Life Science & Biotechnology, Kyungpook National University, Daegu 41566, South Korea
6Brain Science and Engineering Institute, Kyungpook National University, Daegu 41944, South Korea
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Kea Joo Lee
3Department of Structure and Function of Neural Network, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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Sung Bae Lee
2Department of Brain & Cognitive Sciences, DGIST, Daegu, South Korea, 42988
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Kiyoung Kim
7Department of Medical Biotechnology, Soonchunhyang University, Asan, South Korea, 31538
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  • For correspondence: kijang1@kbri.re.kr kiyoung2@sch.ac.kr
Hyung-Jun Kim
1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea, 41068
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  • For correspondence: kijang1@kbri.re.kr kiyoung2@sch.ac.kr
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Abstract

TDP-43 proteinopathy is a common feature in a variety of neurodegenerative disorders including Amyotrophic lateral sclerosis (ALS) cases, Frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease. However, the molecular mechanisms underlying TDP-43-induced neurotoxicity are largely unknown. In this study, we demonstrated that TDP-43 proteinopathy induces impairment in ubiquitin-proteasome system (UPS) evidenced by an accumulation of ubiquitinated proteins and reduction of proteasome activity in neuronal cells. Through kinase inhibitor screening, we identified PTK2 as a suppressor of neurotoxicity induced by UPS impairment. Importantly, PTK2 inhibition significantly reduces ubiquitin aggregates and attenuated TDP-43-induced cytotoxicity in Drosophila model of TDP-43 proteinopathy. We further identified that phosphorylation of p62 at serine 403 (p-p62S403), a key component in the autophagic degradation of poly-ubiquitinated proteins, is increased upon TDP-43 overexpression and dependent on activation of PTK2 in neuronal cells. Moreover, expressing a non-phosphorylated form of p62 (p62S403A) significantly represses accumulation of polyubiquitinated proteins and neurotoxicity induced by TDP-43 overexpression in neuronal cells. In addition, inhibition of TBK1, a kinase which phosphorylates S403 of p62, ameliorates neurotoxicity upon UPS impairment in neuronal cells. Taken together, our data suggest that activation of PTK2-TBK1-p62 axis plays a critical role in the pathogenesis of TDP-43 by regulating neurotoxicity induced by UPS impairment. Therefore, targeting PTK2-TBK1-p62 axis may represent a novel therapeutic intervention for neurodegenerative diseases with TDP-43 proteinopathy.

Abbreviations
ALS
Amyotrophic lateral sclerosis
FTLD
Frontotemporal lobar degeneration
UPS
Ubiquitin proteasome system
ALP
Autophagy lysosomal pathway
SQSTM1
Sequestosome 1
TBK1
TANK-binding kinase 1
CK2
Casein kinase 2
ULK1
Unc-51 like autophagy-activating kinase 1
SOD1
Superoxide dismutase 1
OPTN
Optineurin
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Posted June 25, 2018.
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PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy
Shinrye Lee, Yu-Mi Jeon, Seyeon Kim, Younghwi Kwon, Myungjin Jo, You-Na Jang, Seongsoo Lee, Jaekwang Kim, Sang Ryong Kim, Kea Joo Lee, Sung Bae Lee, Kiyoung Kim, Hyung-Jun Kim
bioRxiv 355446; doi: https://doi.org/10.1101/355446
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PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy
Shinrye Lee, Yu-Mi Jeon, Seyeon Kim, Younghwi Kwon, Myungjin Jo, You-Na Jang, Seongsoo Lee, Jaekwang Kim, Sang Ryong Kim, Kea Joo Lee, Sung Bae Lee, Kiyoung Kim, Hyung-Jun Kim
bioRxiv 355446; doi: https://doi.org/10.1101/355446

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