Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy
Lithium induces clearance of protease resistant prion protein in prion-infected cells by induction of autophagy
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DOI：
10.1111/j.1471-4159.2009.05906.x
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发表时间：
2009-04-01
影响因子：
4.7
通讯作者：
Schaetzl, Hermann M.
中科院分区：
文献类型：
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作者：
Heiseke, Andreas;Aguib, Yasmine;Schaetzl, Hermann M.
几十年来，锂被用于治疗躁狂抑郁症（双相情感障碍）。最近，发现锂诱导自噬，从而促进实验系统中突变亨廷顿蛋白和α-突触核蛋白的清除。我们在这里首次表明，锂显着减少的数量的病理性朊病毒蛋白（PrPSc）在朊病毒感染的神经元和非神经元培养细胞诱导自噬。用3-甲基腺嘌呤（一种有效的自噬抑制剂）处理朊病毒感染的细胞，抵消了锂的抗朊病毒作用，表明自噬诱导介导了PrPSc的降解。锂和雷帕霉素（一种广泛用于诱导自噬的药物）的共同治疗与单独使用任一种药物的治疗相比对PrPSc清除具有累加效应。此外，我们提供的证据表明，减少PrPSc和诱导自噬的能力是常见的不同的锂化合物，而不仅仅是药物氯化锂，通常在临床治疗中使用。此外，我们在这里表明，除了减少PrPSc聚集体，锂诱导的自噬也略有降低细胞朊病毒蛋白的水平。限制细胞朊病毒蛋白转化为PrPSc的底物可能为锂诱导的自噬减少PrPSc提供了另一种机制。
Lithium is used for several decades to treat manic-depressive illness (bipolar affective disorder). Recently, it was found that lithium induces autophagy, thereby promoting the clearance of mutant huntingtin and alpha-synucleins in experimental systems. We show here for the first time that lithium significantly reduces the amount of pathological prion protein (PrPSc) in prion-infected neuronal and non-neuronal cultured cells by inducing autophagy. Treatment of prion-infected cells with 3-methyladenine, a potent inhibitor of autophagy, counteracted the anti-prion effect of lithium, demonstrating that induction of autophagy mediates degradation of PrPSc. Co-treatment with lithium and rapamycin, a drug widely used to induce autophagy, had an additive effect on PrPSc clearance compared to treatment with either drug alone. In addition, we provide evidence that the ability to reduce PrPSc and to induce autophagy is common for diverse lithium compounds, not only for the drug lithium chloride, usually administered in clinical therapy. Furthermore, we show here that besides reduction of PrPSc-aggregates, lithium-induced autophagy also slightly reduces the levels of cellular prion protein. Limiting the substrate available for conversion of cellular prion protein into PrPSc may provide an additional mechanism for reduction of PrPSc by lithium-induced autophagy.