GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib
GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib
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GSK-3β 导致帕金森病多巴胺能神经元死亡：来自条件性基因敲除小鼠和 Tideglusib 的证据
DOI：
10.3389/fnmol.2020.00081
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发表时间：
2020-06-03
影响因子：
4.8
通讯作者：
Huang, Qiaoying
中科院分区：
文献类型：
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作者：
Li, Junyu;Ma, Shanshan;Huang, Qiaoying
糖原合成酶激酶-3（GSK-3）失调与黑质多巴胺能神经变性有关，后者是帕金森病（PD）的主要病理特征之一。GSK-3 α和GSK-3 β这两种亚型都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-3 β对PD发病机制的作用，而GSK-3 α的作用在很大程度上被忽视。在这里，我们证实了在小鼠暴露于1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）后，GSK-3 α和GSK-3 β在负作用调节丝氨酸处脱磷酸化，表明在黑质多巴胺能神经元中选择性地激活激酶。为了确定GSK-3 α和GSK-3 β是否在调节帕金森病多巴胺能细胞死亡中显示功能冗余，我们分别分析了多巴胺能神经元特异性Gsk 3anull（Gsk 3a（Delta Dat））和Gsk 3b null（Gsk 3b（Delta Dat））小鼠。我们发现，Gsk 3b（Delta Dat），而不是Gsk 3a（Delta Dat），显示出对MPTP损伤的显著抗性，揭示了GSK-3 α和GSK-3 β在PD发病机制中的非冗余性。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tideglusib的神经保护作用。给予较高剂量（200 mg/kg和500 mg/kg）的tideglusib显示出显著的神经保护作用，而50 mg/kg tideglusib未能预防MPTP毒性引起的多巴胺能神经变性。给予200 mg/kg tideglusib可改善MPTP治疗小鼠的运动症状。总之，这些数据表明GSK-3 β而不是GSK-3 α对帕金森病神经变性至关重要。我们的数据支持GSK-3 β作为PD潜在治疗靶点的观点，替德格鲁西布将成为PD神经保护治疗的候选药物。
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-3 alpha and GSK-3 beta, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3 beta on PD pathogenesis, while the role of GSK-3 alpha has been largely overlooked. Here, we reportin situobservations that both GSK-3 alpha and GSK-3 beta 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-3 alpha and GSK-3 beta display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3anull (Gsk3a(Delta Dat)) and Gsk3b null (Gsk3b(Delta Dat)) mice, respectively. We found that Gsk3b(Delta Dat), but not Gsk3a(Delta Dat), showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3 alpha and GSK-3 beta 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-3 beta and not GSK-3 alpha is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3 beta acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.