The upregulated α-synuclein (α-syn) and Tau co-occur in methamphetamine (METH) abusers' brains. Here, we designed experiments mainly to investigate whether α-syn and Tau interact in METH exposure. We detected the expression of α-syn, total Tau, and phosphorylation of Tau at Serine 396 (pSer396 Tau) under in vitro and in vivo conditions after METH exposure to determine the co-occurrence of α-syn and Tau. We also explored the effect of α-syn or Tau on one another by silencing and knocking-out one of them in METH treatment. We found that METH increased the α-syn, total Tau, and pSer396 Tau protein level in SH-SY5Y cells, primary cultured neurons, and in mice brains. In additional, reducing α-syn level can relieve and even normalize the pSer396 Tau and total Tau overexpression after treatment of METH. Furthermore, knocking out Tau can effectively inhibit METH induced overexpression of α-syn in mice brains. Finally, knocking out α-syn or Tau can effectively reduce METH-induced neurotoxicity in mice brains. This research could provide potential therapeutic approaches targeting the vicious circle between α-syn and Tau in METH abusers and patients with neurodegenerative disorders.

中文翻译：

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α-突触核蛋白和 Tau 在甲基苯丙胺诱导的体内和体外神经毒性中的作用

上调的 α-突触核蛋白 (α-syn) 和 Tau 共同出现在甲基苯丙胺 (METH) 滥用者的大脑中。在这里，我们设计的实验主要是为了研究 α-syn 和 Tau 在 METH 暴露中是否相互作用。我们在体外和体内条件下检测了 α-syn 的表达、总 Tau 和丝氨酸 396 (pSer396 Tau) 的磷酸化，以确定 α-syn 和 Tau 的共存。我们还通过在 METH 治疗中沉默和敲除其中一个来探索 α-syn 或 Tau 对彼此的影响。我们发现 METH 增加了 SH-SY5Y 细胞、原代培养神经元和小鼠大脑中的 α-syn、总 Tau 和 pSer396 Tau 蛋白水平。此外，降低 α-syn 水平可以减轻甚至使 METH 治疗后 pSer396 Tau 和总 Tau 过表达正常化。此外，敲除 Tau 可以有效抑制 METH 诱导的小鼠大脑中 α-syn 的过度表达。最后，敲除 α-syn 或 Tau 可以有效降低 METH 诱导的小鼠大脑神经毒性。这项研究可以提供针对 METH 滥用者和神经退行性疾病患者中 α-syn 和 Tau 之间恶性循环的潜在治疗方法。