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Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser...

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Autores principales: Chi, Hao, Sun, Lee, Shiu, Ren-Huei, Han, Rui, Hsieh, Chien-Ping, Wei, Tzu-Min, Lo, Chung-Chuan, Chang, Hui-Yun, Sang, Tzu-Kang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417559/
https://www.ncbi.nlm.nih.gov/pubmed/32778728
http://dx.doi.org/10.1038/s41598-020-70423-1
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author Chi, Hao
Sun, Lee
Shiu, Ren-Huei
Han, Rui
Hsieh, Chien-Ping
Wei, Tzu-Min
Lo, Chung-Chuan
Chang, Hui-Yun
Sang, Tzu-Kang
author_facet Chi, Hao
Sun, Lee
Shiu, Ren-Huei
Han, Rui
Hsieh, Chien-Ping
Wei, Tzu-Min
Lo, Chung-Chuan
Chang, Hui-Yun
Sang, Tzu-Kang
author_sort Chi, Hao
collection PubMed
description Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser/Thr residues to simulate hyperphosphorylation, we show that despite severe neurodegeneration in full-length tau, with the truncation at Asp421, the toxicity is ameliorated. Cytological and biochemical analyses reveal that hyperphosphorylated full-length tau distributes in the soma, the axon, and the axonal terminal without evident distinction, whereas the Asp421-truncated version is mostly restricted from the axonal terminal. This discrepancy is correlated with the fact that fly expressing hyperphosphorylated full-length tau, but not Asp421-cleaved one, develops axonopathy lesions, including axonal spheroids and aberrant actin accumulations. The reduced presence of hyperphosphorylated tau in the axonal terminal is corroborated with the observation that flies expressing Asp421-truncated variants showed less motor deficit, suggesting synaptic function is preserved. The Asp421 cleavage of tau is a proteolytic product commonly found in the neurofibrillary tangles. Our finding suggests the coordination of different posttranslational modifications on tau may have an unexpected impact on the protein subcellular localization and cytotoxicity, which may be valuable when considering tau for therapeutic purposes.
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spelling pubmed-74175592020-08-11 Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model Chi, Hao Sun, Lee Shiu, Ren-Huei Han, Rui Hsieh, Chien-Ping Wei, Tzu-Min Lo, Chung-Chuan Chang, Hui-Yun Sang, Tzu-Kang Sci Rep Article Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser/Thr residues to simulate hyperphosphorylation, we show that despite severe neurodegeneration in full-length tau, with the truncation at Asp421, the toxicity is ameliorated. Cytological and biochemical analyses reveal that hyperphosphorylated full-length tau distributes in the soma, the axon, and the axonal terminal without evident distinction, whereas the Asp421-truncated version is mostly restricted from the axonal terminal. This discrepancy is correlated with the fact that fly expressing hyperphosphorylated full-length tau, but not Asp421-cleaved one, develops axonopathy lesions, including axonal spheroids and aberrant actin accumulations. The reduced presence of hyperphosphorylated tau in the axonal terminal is corroborated with the observation that flies expressing Asp421-truncated variants showed less motor deficit, suggesting synaptic function is preserved. The Asp421 cleavage of tau is a proteolytic product commonly found in the neurofibrillary tangles. Our finding suggests the coordination of different posttranslational modifications on tau may have an unexpected impact on the protein subcellular localization and cytotoxicity, which may be valuable when considering tau for therapeutic purposes. Nature Publishing Group UK 2020-08-10 /pmc/articles/PMC7417559/ /pubmed/32778728 http://dx.doi.org/10.1038/s41598-020-70423-1 Text en © The Author(s) 2020 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chi, Hao
Sun, Lee
Shiu, Ren-Huei
Han, Rui
Hsieh, Chien-Ping
Wei, Tzu-Min
Lo, Chung-Chuan
Chang, Hui-Yun
Sang, Tzu-Kang
Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model
title Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model
title_full Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model
title_fullStr Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model
title_full_unstemmed Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model
title_short Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model
title_sort cleavage of human tau at asp421 inhibits hyperphosphorylated tau induced pathology in a drosophila model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417559/
https://www.ncbi.nlm.nih.gov/pubmed/32778728
http://dx.doi.org/10.1038/s41598-020-70423-1
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