Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, El-Gomhourya Street, Mansoura, 36551, Egypt.
Department of Toxicology, Mansoura University, Mansoura, Egypt.
Metab Brain Dis. 2018 Apr;33(2):583-587. doi: 10.1007/s11011-017-0137-7. Epub 2017 Oct 27.
Tauopathy comprises a group of disorders caused by abnormal aggregates of tau protein. In these disorders phosphorylated tau protein tends to accumulate inside neuronal cells (soma) instead of the normal axonal distribution of tau. A suggested therapeutic strategy for tauopathy is to induce autophagy to increase the ability to get rid of the unwanted tau aggregates. One of the key controllers of autophagy is mTOR. Blocking mTOR leads to stimulation of autophagy. Recently, unravelling molecular structure of mTOR showed that it is formed of two subunits: mTORC1/C2. So, blocking both subunits of mTOR seems more attractive as it will explore all abilities of mTOR molecule. In the present study, we report using pp242 which is a dual mTORC1/C2 blocker in cellular model of tauopathy using LUHMES cell line. Adding fenazaquin to LUHMES cells induced tauopathy in the form of increased phospho tau aggregates. Moreover, fenazaquin treated cells showed the characteristic somatic redistribution of tau. PP242 use in the present tauopathy model reversed the pathology significantly without observable cellular toxicity for the used dosage of 1000 nM. The present study suggests the possible use of pp242 as a dual mTOR blocker to treat tauopathy.
tau 病包括一组由 tau 蛋白异常聚集引起的疾病。在这些疾病中，磷酸化 tau 蛋白往往在神经元细胞（体）内积累，而不是正常的 tau 蛋白在轴突中的分布。tau 病的一种治疗策略是诱导自噬，以提高清除不需要的 tau 聚集物的能力。自噬的一个关键控制器是 mTOR。阻断 mTOR 会导致自噬的刺激。最近，mTOR 的分子结构的揭示表明它由两个亚基组成：mTORC1/C2。因此，阻断 mTOR 的两个亚基似乎更有吸引力，因为它将探索 mTOR 分子的所有能力。在本研究中，我们报告了使用 pp242 在使用 LUHMES 细胞系的 tau 病细胞模型中作为 mTORC1/C2 双重阻断剂的情况。向 LUHMES 细胞中添加芬氮嗪会以增加磷酸化 tau 聚集的形式诱导 tau 病。此外，用芬氮嗪处理的细胞显示 tau 的特征性体分布重新分布。在本 tau 病模型中使用 pp242 显著逆转了病理，而使用的 1000 nM 剂量没有观察到明显的细胞毒性。本研究表明，pp242 可能作为一种 mTOR 双重阻断剂用于治疗 tau 病。
