我们前期研究首次在帕金森病(PD)小鼠中借助GSK-3β抑制剂和多巴胺能神经元(DAN)特异敲除鼠(Gsk3b cKO)证实GSK-3β是介导DAN死亡的关键激酶。最近发现Gsk3b cKO明显抑制PD小鼠DAN促死亡转录因子c-Jun蛋白上调而不抑制其mRNA，提示GSK-3β介导c-Jun蛋白稳定。Fbw7是促c-Jun降解的E3连接酶。我们发现PD鼠DAN核内Fbw7减少，可被Gsk3b cKO逆转，且GSK-3β定位于胞浆，是否GSK-3β通过抑制Fbw7核定位稳定c-Jun？文献报道Fbw7可被假底物竞争招募，而其假底物模序符合GSK-3β底物序列，磷酸化促进招募。通过分析胞浆GSK-3β底物，我们提出科学假设：PD时DAN中GSK-3β磷酸化底物如tau，后者作为Fbw7假底物竞争抑制c-Jun降解，导致DAN死亡。本项目拟验证该假设，为以GSK-3β为靶治疗PD提供科学依据。

Our previous work has demonstrated for the first time that GSK-3β plays a critical role in dopaminergic neuronal death in Parkinsonian mouse model by using GSK-3β inhibitors and conditional knockout mice (Gsk3b cKO). We have observed that Gsk3b cKO inhibits upregulation of the protein levels but not the mRNA levels of c-Jun during dopaminergic neurodegeneration, suggesting that GSK-3β increases c-Jun protein stability. It is known that E3 ligase Fbw7 ubiquitinates c-Jun to promote its degradation. Here we find loss of Fbw7 protein expression within the nuclei of nigra dopaminergic neurons in Parkinsonian mice, and Gsk3b cKO attenuates this loss. We thus raise the question that whether GSK-3β upregulates c-Jun by regulation involving subcellular localization of Fbw7. There have been reported Fbw7 exemplifies this type of control. Fbw7 recognises a conserved phosphodegron motif which is often phosphorylated by GSK-3β. Via further analysis, we propose that during dopaminergic neurodegeneration, GSK-3β phosphorylates cytosolic substrates, such as tau. Phosphorylated tau might act like pseudosubstrate directly recruiting Fbw7 and exert competitive inhibition of c-Jun degradation, leading to dopaminergic neuronal death. In this project, we plan to clarify the mechanism(s) underlying GSK-3β-mediated upregulation of c-Jun by using genetically engineered mice and the methods of molecular neurobiology, and to provide scientific evidence to establish GSK-3β as a new therapeutic target of neuroprotection for Parkinson’s disease.