Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Biochem Biophys Res Commun. 2021 Mar 5;543:65-71. doi: 10.1016/j.bbrc.2020.12.113. Epub 2021 Jan 28.
Different conformational strains of tau have been implicated in the clinicopathological heterogeneity of tauopathies. In this study, we hypothesized that distinct strains are degraded in a different manner. Lithium, a drug for bipolar disorder, had previously been reported to reduce aggregation-prone protein content by promoting autophagy. Here, we assessed the effects of lithium on tau aggregates using different tauopathy brain seeds. SH-SY5Y cells were transfected with C-terminal tau fragment Tau-CTF24 (residues 243-441), and Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain seeds were introduced. After 48-h lithium treatment, sarkosyl-insoluble fractions were prepared. Lithium treatment was found to reduce the amount of insoluble tau and p62, and increase LC3-II levels along with the number of autophagic vacuoles in AD-seeded cells. The effects were lower in case of CBD seeds, and comparable between PSP and AD seeds. An inhibitor of myo-inositol monophosphatase (IMPase) also demonstrated similar effects. Overall, the study suggested that aggregated tau protein is degraded by lithium-induced autophagy, influencing IMPase in a strain-specific manner.
不同构象的 tau 已被牵连到 tau 病的临床病理异质性中。在这项研究中，我们假设不同的构象以不同的方式降解。锂是一种用于治疗双相情感障碍的药物，先前曾被报道通过促进自噬来减少聚集倾向蛋白的含量。在这里，我们使用不同的 tau 病脑种子评估了锂对 tau 聚集物的影响。SH-SY5Y 细胞转染了 C 端 tau 片段 Tau-CTF24（残基 243-441），并引入了阿尔茨海默病（AD）、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）脑种子。锂处理 48 小时后，制备了 Sarkosyl 不溶性级分。锂处理降低了 AD 种子细胞中不溶性 tau 和 p62 的量，并增加了 LC3-II 水平和自噬小体的数量。在 CBD 种子的情况下，效果较低，而在 PSP 和 AD 种子之间则相当。肌醇单磷酸酶（IMPase）的抑制剂也表现出类似的效果。总体而言，该研究表明，聚集的 tau 蛋白通过锂诱导的自噬降解，以特定于构象的方式影响 IMPase。
