Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson’s disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3a^ΔDat) and Gsk3b null (Gsk3b^ΔDat) mice, respectively. We found that Gsk3b^ΔDat, but not Gsk3a^ΔDat, showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.

糖原合酶激酶3（GSK-3）失调与黑质多巴胺能神经变性有关，这是帕金森氏病（PD）的主要病理特征之一。两种同工型GSK-3α和GSK-3β均被认为在神经元死亡中起有害作用。迄今为止，一些研究集中在GSK-3β在PD发病机理中的作用，而GSK-3α的作用已被大大忽略。在这里，我们报告原位观察到，在小鼠暴露于1-甲基-4-苯基-1,2,3,6-四氢吡啶后，在黑色素多巴胺能神经元中，GSK-3α和GSK-3β均在负性调节丝氨酸上被去磷酸化，表明激酶激活（MPTP）。为了确定GSK-3α和GSK-3β在调节帕金森氏多巴胺能细胞死亡中是否显示功能冗余，我们分析了多巴胺能神经元特异性Gsk3a 空值 （Gsk3a^Δ达特）和 Gsk3b 空值 （Gsk3b^Δ达特）小鼠。我们发现 Gsk3b^Δ达特， 但不是 Gsk3a^Δ达特，显示出对MPTP侵害的显着抗性，揭示了PD发病机理中GSK-3α和GSK-3β的非冗余性。此外，我们在PD的MPTP模型中测试了临床上最先进的GSK-3抑制剂替格鲁西布的神经保护作用。给予更高剂量（200 mg / kg和500 mg / kg）的替格鲁司表现出显着的神经保护作用，而50 mg / kg替格鲁司不能阻止MPTP毒性引起的多巴胺能神经退行性变。给予200 mg / kg替格鲁司改善了MPTP治疗的小鼠的运动症状。这些数据一起证明了GSK-3β而不是GSK-3α对帕金森氏神经变性至关重要。我们的数据支持这样的观点，即GSK-3β可以作为PD的潜在治疗靶点，而tideglusib将成为PD神经保护疗法的候选药物。