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

作者：Mengzhu Li, Enjie Liu, Qiuzhi Zhou, Shihong Li, Shijie Liu, Haitao Yu, Qihang Pan, Fei Sun, Ting He, Wei-Jin Wang, Dan Ke, Yu-Qi Feng, Jun Li, Jian‐Zhi Wang · 发表于：Military Medical Research · 年份：2022 · DOI：10.1186/s40779-022-00396-x · 被引用次数：24 · 研究领域：Autophagy in Disease and Therapy、Alzheimer's disease research and treatments、Parkinson's Disease Mechanisms and Treatments

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: -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-lik...