p62/SQSTM1 is a multifunctional, cytoplasmic protein with fundamental roles in autophagy and antioxidant responses. Here we showed that p62 translocated from the cytoplasm to the nucleus in nigral dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrid (MPTP)-induced mouse model of Parkinson’s disease (PD). We found that p62 was physically associated with glycogen synthase kinase (GSK)-3β, a serine/threonine protein kinase implicated in dopaminergic neurodegeneration in PD, and that MPTP treatment promoted dissociation of the complex in mice. Conditional knockout of GSK-3 prevented nuclear translocation of p62, suggesting that this translocation was detrimental to dopaminergic neurons. p62 knockout mice were used to investigate the role of p62 in MPTP-induced neuronal death. Knockout of p62 aggravated neuronal injury induced by MPTP intoxication, suggesting that p62 plays an important role in dopaminergic cell survival in stress conditions. Together, our data demonstrate that GSK-3 mediates nuclear translocation of p62 during MPTP-induced parkinsonian neurodegeneration. These findings shed new light on the role of the cytoplasmic-nuclear shuttling of p62 and the mechanism underlying GSK-3-depedent neuronal death in PD pathogenesis.

p62/SQSTM1 是一种多功能的细胞质蛋白，在自噬和抗氧化反应中具有重要作用。在这里，我们发现在 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的帕金森病 (PD) 小鼠模型中，p62 从细胞质转移到黑质多巴胺能神经元的细胞核。我们发现 p62 与糖原合酶激酶 (GSK)-3β 物理相关，糖原合酶激酶 (GSK)-3β 是一种丝氨酸/苏氨酸蛋白激酶，与 PD 中的多巴胺能神经变性有关，并且 MPTP 治疗促进了小鼠体内复合物的解离。GSK-3 的条件性敲除阻止了 p62 的核易位，表明这种易位对多巴胺能神经元有害。p62 敲除小鼠用于研究 p62 在 MPTP 诱导的神经元死亡中的作用。敲除 p62 会加重 MPTP 中毒诱导的神经元损伤，这表明 p62 在应激条件下的多巴胺能细胞存活中起重要作用。总之，我们的数据表明 GSK-3 在 MPTP 诱导的帕金森神经变性期间介导 p62 的核易位。这些发现为 p62 的细胞质 - 核穿梭的作用以及 GSK-3 依赖性神经元死亡在 PD 发病机制中的作用提供了新的启示。