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BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease

Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is...

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Autores principales: Zhang, Lu, Fang, Yu, Zhao, Xinyu, Zheng, Yake, Ma, Yunqing, Li, Shuang, Huang, Zhi, Li, Lihao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342531/
https://www.ncbi.nlm.nih.gov/pubmed/34354038
http://dx.doi.org/10.1038/s41398-021-01427-2
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author Zhang, Lu
Fang, Yu
Zhao, Xinyu
Zheng, Yake
Ma, Yunqing
Li, Shuang
Huang, Zhi
Li, Lihao
author_facet Zhang, Lu
Fang, Yu
Zhao, Xinyu
Zheng, Yake
Ma, Yunqing
Li, Shuang
Huang, Zhi
Li, Lihao
author_sort Zhang, Lu
collection PubMed
description Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome–lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome–lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD.
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spelling pubmed-83425312021-08-20 BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease Zhang, Lu Fang, Yu Zhao, Xinyu Zheng, Yake Ma, Yunqing Li, Shuang Huang, Zhi Li, Lihao Transl Psychiatry Article Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer’s disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome–lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome–lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD. Nature Publishing Group UK 2021-08-05 /pmc/articles/PMC8342531/ /pubmed/34354038 http://dx.doi.org/10.1038/s41398-021-01427-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Lu
Fang, Yu
Zhao, Xinyu
Zheng, Yake
Ma, Yunqing
Li, Shuang
Huang, Zhi
Li, Lihao
BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
title BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
title_full BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
title_fullStr BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
title_full_unstemmed BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
title_short BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer’s disease
title_sort bruce silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342531/
https://www.ncbi.nlm.nih.gov/pubmed/34354038
http://dx.doi.org/10.1038/s41398-021-01427-2
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