Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during MAPT/Tau-induced proteotoxic stress
Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during MAPT/Tau-induced proteotoxic stress
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DOI：
10.1080/15548627.2021.1875611
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发表时间：
2021-01-25
期刊：
影响因子：
13.3
通讯作者：
Giustiniani, Julien
中科院分区：
文献类型：
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作者：
Chambraud, Beatrice;Daguinot, Corentin;Giustiniani, Julien
自噬-溶酶体蛋白降解的缺陷被认为与多种神经退行性疾病的发病机制以及阿尔茨海默病 (AD) 中 MAPT/Tau 等易聚集蛋白的积累有关。我们之前展示了亲免素 FKBP4/FKBP52 在健康人类神经元溶酶体系统中的定位，表明其在溶酶体功能中的可能作用。我们还发现 AD 脑神经元中 FKBP4 水平降低与异常 MAPT 积累和聚集相关。在这项研究中，我们证明人神经元细胞系（SH-SY5Y）和人MAPT（P301S）转基因小鼠的背根神经节（DRG）神经元中FKBP4的减少影响了MAPT诱导的蛋白毒性应激条件下的自噬-溶酶体系统的功能。我们发现 SH-SY5Y 细胞中 MAPT 的急性积累诱导了溶酶体的核周聚集，触发了 FKBP4 在簇周围的定位及其与 MAPT 和 MAP1LC3/LC3 阳性自噬囊泡的共定位；在一些 AD 脑神经元中检测到类似的 FKBP4 定位。我们证明 FKBP4 减少了溶酶体聚集的改变，同时 MAPT 和 MAP1LC3 分泌增加。尽管异位FKBP4表达在我们的实验条件下不能诱导自噬，但它在SH-SY5Y细胞中MAPT积累后阻止MAPT分泌，这意味着FKBP4对MAPT分泌具有调节作用。最后，我们观察到 FKBP4 缺陷降低了 MAP1LC3-II 的表达，并在小鼠 DRG 神经元的长期应激过程中引发 MAPT 积累。我们假设在 AD 脑神经元中观察到的 FKBP4 异常减少可能会阻碍自噬效率，并通过在 MAPT 发病过程中调节 MAPT 分泌和积累来促进 tau 蛋白病的进展。
Defects of autophagy-lysosomal protein degradation are thought to contribute to the pathogenesis of several neurodegenerative diseases, and the accumulation of aggregation prone proteins such as MAPT/Tau in Alzheimer disease (AD). We previously showed the localization of the immunophilin FKBP4/FKBP52 in the lysosomal system of healthy human neurons suggesting its possible role in lysosome function. We also showed that decreased FKBP4 levels in AD brain neurons correlate with abnormal MAPT accumulation and aggregation. In this study, we demonstrate that FKBP4 decrease in a human neuronal cell line (SH-SY5Y) and in dorsal root ganglion (DRG) neurons from human MAPT(P301S) transgenic mice affected the function of the autophagy-lysosomal system under MAPT induced proteotoxic stress conditions. We show that acute MAPT accumulation in SH-SY5Y cells induced perinuclear clustering of lysosomes, triggered FKBP4 localization around the clusters and its colocalization with MAPT and MAP1LC3/LC3-positive autophagic vesicles; a similar FKBP4 localization was detected in some AD brain neurons. We demonstrate that FKBP4 decrease altered lysosomal clustering along with MAPT and MAP1LC3 secretion increase. Although ectopic FKBP4 expression could not induce autophagy under our experimental conditions, it prevented MAPT secretion after MAPT accumulation in SH-SY5Y cells implying a regulatory role of FKBP4 on MAPT secretion. Finally, we observe that FKBP4 deficiency decreased MAP1LC3-II expression and provoked MAPT accumulation during long-term stress in mouse DRG neurons. We hypothesize that the abnormal FKBP4 decrease observed in AD brain neurons might hinder autophagy efficiency and contribute to the progression of the tauopathy by modulating MAPT secretion and accumulation during MAPT pathogenesis.