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

• Published in: Translational psychiatry Vol. 11; no. 1; pp. 421 - 11
• Main Authors: Zhang, Lu, Fang, Yu, Zhao, Xinyu, Zheng, Yake, Ma, Yunqing, Li, Shuang, Huang, Zhi, Li, Lihao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.08.2021; Nature Publishing Group
• Subjects: 631/378; 692/53; Alzheimer Disease - genetics; Alzheimer's disease; Animals; Autophagosomes; Behavioral Sciences; Biological Psychology; Brain-Derived Neurotrophic Factor; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Kinases; Lysosomes; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; MicroRNAs; Neurosciences; Pharmacotherapy; Psychiatry; Ubiquitin-Conjugating Enzymes
• DOI: 10.1038/s41398-021-01427-2
• ISSN: 2158-3188

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.