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Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling

BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau ov...

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Autores principales: Li, Meng-Zhu, Liu, En-Jie, Zhou, Qiu-Zhi, Li, Shi-Hong, Liu, Shi-Jie, Yu, Hai-Tao, Pan, Qi-Hang, Sun, Fei, He, Ting, Wang, Wei-Jin, Ke, Dan, Feng, Yu-Qi, Li, Jun, Wang, Jian-Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264508/
https://www.ncbi.nlm.nih.gov/pubmed/35799293
http://dx.doi.org/10.1186/s40779-022-00396-x
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author Li, Meng-Zhu
Liu, En-Jie
Zhou, Qiu-Zhi
Li, Shi-Hong
Liu, Shi-Jie
Yu, Hai-Tao
Pan, Qi-Hang
Sun, Fei
He, Ting
Wang, Wei-Jin
Ke, Dan
Feng, Yu-Qi
Li, Jun
Wang, Jian-Zhi
author_facet Li, Meng-Zhu
Liu, En-Jie
Zhou, Qiu-Zhi
Li, Shi-Hong
Liu, Shi-Jie
Yu, Hai-Tao
Pan, Qi-Hang
Sun, Fei
He, Ting
Wang, Wei-Jin
Ke, Dan
Feng, Yu-Qi
Li, Jun
Wang, Jian-Zhi
author_sort Li, Meng-Zhu
collection PubMed
description BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H(+)-ATPase (v-ATPase) activity, respectively, which were analysed by One‐way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One‐way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies.
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spelling pubmed-92645082022-07-09 Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling Li, Meng-Zhu Liu, En-Jie Zhou, Qiu-Zhi Li, Shi-Hong Liu, Shi-Jie Yu, Hai-Tao Pan, Qi-Hang Sun, Fei He, Ting Wang, Wei-Jin Ke, Dan Feng, Yu-Qi Li, Jun Wang, Jian-Zhi Mil Med Res Research BACKGROUND: Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease (AD). This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy. METHODS: The primary hippocampal neurons, N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy, which was analysed by Student's two-tailed t-test. The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1 (mTORC1) activity and the vacuolar H(+)-ATPase (v-ATPase) activity, respectively, which were analysed by One‐way ANOVA with post hoc tests. The Western blotting, co-immunoprecipitation and immunofluorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations, as analysed by Student's two-tailed t-test or One‐way ANOVA with post hoc tests. The autophagosome formation was detected by immunofluorescence staining and transmission electron microscopy. The amino acids (AA) levels were detected by high performance liquid chromatography (HPLC). RESULTS: We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits. Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1 (PRD-TIA1) and this association significantly increased the intercellular level of amino acids (Leucine, P = 0.0038; Glutamic acid, P = 0.0348; Alanine, P = 0.0037; Glycine, P = 0.0104), with concordant upregulation of mTORC1 activity [phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4EBP1), P < 0.0001; phosphorylated 70 kDa ribosomal protein S6 kinase 1 (p-p70S6K1), P = 0.0001, phosphorylated unc-51-like autophagy-activating kinase 1 (p-ULK1), P = 0.0015] and inhibition of autophagosome formation [microtubule-associated protein light chain 3 II (LC3 II), P = 0.0073; LC3 puncta, P < 0.0001]. As expected, this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation. Importantly, we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1, downregulating the endogenous TIA1 expression by shRNA, or downregulating tau protein level by a small proteolysis targeting chimera (PROTAC) could remarkably attenuate tau-induced autophagy impairment. CONCLUSIONS: Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway, and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treatment and that of related tauopathies. BioMed Central 2022-07-07 /pmc/articles/PMC9264508/ /pubmed/35799293 http://dx.doi.org/10.1186/s40779-022-00396-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Li, Meng-Zhu
Liu, En-Jie
Zhou, Qiu-Zhi
Li, Shi-Hong
Liu, Shi-Jie
Yu, Hai-Tao
Pan, Qi-Hang
Sun, Fei
He, Ting
Wang, Wei-Jin
Ke, Dan
Feng, Yu-Qi
Li, Jun
Wang, Jian-Zhi
Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
title Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
title_full Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
title_fullStr Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
title_full_unstemmed Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
title_short Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling
title_sort intracellular accumulation of tau inhibits autophagosome formation by activating tia1-amino acid-mtorc1 signaling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9264508/
https://www.ncbi.nlm.nih.gov/pubmed/35799293
http://dx.doi.org/10.1186/s40779-022-00396-x
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