Fang Wei, Gao Guodong, Zhao Haikang, Xia Yi, Guo Xiaodong, Li Nan, Li Yuqian, Yang Yang, Chen Lei, Wang Qiang, Li Lihong
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi׳an City 710038, PR China.
The second Affiliated Hospital,Xi׳an Medical University, Xi׳an City 710038, PR China.
Brain Res. 2015 Mar 30;1602:9-19. doi: 10.1016/j.brainres.2014.08.030. Epub 2014 Aug 21.
Parkinson׳s disease (PD) is the most common neurodegenerative disease of the basal ganglia. Earlier reports suggest that the main pathological change in PD is due to apoptosis of dopaminergic neuronal soma in the substantia nigra (SN). The therapies for PD are also largely focused on the prevention of degeneration of the neuronal soma. However, these treatments can only provide temporary relief by delaying the progression of the disease and are therefore unable to prevent the long term neurodegeneration process. This limitation of the existing therapeutic treatment indicates that there may be other causes that either occur earlier or are independent of apoptosis of neuronal soma. Previous studies have shown that axon degeneration may play an important role in PD, and that this may occur at an early stage of the disease. Thus, preventing axon degeneration may be a potential new approach for therapeutic treatment for PD and future therapies can be useful if emphasis is given on the mechanisms of axon degeneration. It has been recognized that microtubule disassembly leads to axon degeneration because the depolymerized microtubules are more likely to be degraded. Previous studies have shown that glycogen synthase kinase-3β (GSK-3β)/collapsin response mediator protein 2 (CRMP-2) signaling pathway could be regulated by Akt for axonal-dendritic polarity. CRMP-2 is critical for specifying axon/dendrite fate possibly by promoting neurite elongation via microtubule assembly. However, whether Akt could regulate GSK-3β/CRMP-2 pathway and the possible effects of this regulation is unclear in dopaminergic axon degeneration induced by 1-methyl-4-phenylpyridiniumion (MPP+). In this study, we observe the degeneration of axon and neuronal soma by scanning electron microscope and tyrosine hydroxylase staining (TH) using a PD model in dopaminergic neurons in vitro. In addition to this, we detect the expression of total and phosphorylated form of Akt, GSK-3β and CRMP-2, as well as the axonal injury marker amyloid precursor protein (APP). From our studies, we observe that axon degeneration is a characteristic feature in the cascade of events that follow when neurons are induced by MPP+. This degeneration process occurs earlier in case of PD and is more severe than the degeneration of the neuronal soma and Akt/ GSK-3β/CRMP-2 pathway is involved in this process.
帕金森病（PD）是基底神经节最常见的神经退行性疾病。早期报告表明，PD的主要病理变化是由于黑质（SN）中多巴胺能神经元胞体的凋亡。PD的治疗也主要集中在预防神经元胞体的退化。然而，这些治疗只能通过延缓疾病进展提供暂时缓解，因此无法阻止长期的神经退行性变过程。现有治疗方法的这一局限性表明，可能存在其他更早发生或与神经元胞体凋亡无关的原因。先前的研究表明，轴突退化可能在PD中起重要作用，并且可能在疾病的早期阶段发生。因此，预防轴突退化可能是PD治疗的一种潜在新方法，如果重视轴突退化机制，未来的治疗可能会有用。人们已经认识到微管解聚会导致轴突退化，因为解聚的微管更容易被降解。先前的研究表明，糖原合酶激酶-3β（GSK-3β）/塌陷反应介导蛋白2（CRMP-2）信号通路可由Akt调节以实现轴突-树突极性。CRMP-2可能通过促进微管组装的神经突伸长对确定轴突/树突命运至关重要。然而，在1-甲基-4-苯基吡啶离子（MPP+）诱导的多巴胺能轴突退化中，Akt是否能调节GSK-3β/CRMP-2通路以及这种调节的可能作用尚不清楚。在本研究中，我们使用体外多巴胺能神经元的PD模型，通过扫描电子显微镜和酪氨酸羟化酶染色（TH）观察轴突和神经元胞体的退化。除此之外，我们检测Akt、GSK-3β和CRMP-2的总形式和磷酸化形式的表达，以及轴突损伤标志物淀粉样前体蛋白（APP）。从我们的研究中，我们观察到轴突退化是MPP+诱导神经元后一系列事件中的一个特征。在PD情况下，这种退化过程更早发生，并且比神经元胞体的退化更严重，Akt/GSK-3β/CRMP-2通路参与了这一过程。
