Ding H, Underwood R, Lavalley N, Yacoubian T A
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, USA.
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, USA.
Neuroscience. 2015 Oct 29;307:73-82. doi: 10.1016/j.neuroscience.2015.08.042. Epub 2015 Aug 24.
14-3-3s are a highly conserved protein family that plays important roles in cell survival and interact with several proteins implicated in Parkinson's disease (PD). Disruption of 14-3-3 expression and function has been implicated in the pathogenesis of PD. We have previously shown that increasing the expression level of 14-3-3θ is protective against rotenone and 1-methyl-4-phenylpyridinium (MPP(+)) in cultured cells. Here, we extend our studies to examine the effects of 14-3-3s in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We first investigated whether targeted nigral 14-3-3θ overexpression mediated by adeno-associated virus offers neuroprotection against MPTP-induced toxicity. 14-3-3θ overexpression using this approach did not reduce MPTP-induced dopaminergic cell loss in the substantia nigra nor the depletion of dopamine (DA) and its metabolites in the striatum at three weeks after MPTP administration. However, 14-3-3θ-overexpressing mice showed a later partial recovery in striatal DA metabolites at eight weeks after MPTP administration compared to controls, suggesting that 14-3-3θ overexpression may help in the functional recovery of those dopaminergic neurons that survive. Conversely, we investigated whether disrupting 14-3-3 function in transgenic mice expressing the pan 14-3-3 inhibitor difopein exacerbates MPTP-induced toxicity. We found that difopein expression promoted dopaminergic cell loss in response to MPTP treatment. Together, these findings suggest that 14-3-3θ overexpression promotes recovery of DA metabolites whereas 14-3-3 inhibition exacerbates neuron loss in the MPTP mouse model of PD.
14-3-3s是一个高度保守的蛋白质家族，在细胞存活中发挥重要作用，并与帕金森病（PD）相关的多种蛋白质相互作用。14-3-3表达和功能的破坏与PD的发病机制有关。我们之前已经表明，提高14-3-3θ的表达水平对培养细胞中的鱼藤酮和1-甲基-4-苯基吡啶鎓（MPP(+)）具有保护作用。在此，我们扩展研究以检查14-3-3s在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的PD小鼠模型中的作用。我们首先研究了腺相关病毒介导的靶向黑质14-3-3θ过表达是否能对MPTP诱导的毒性提供神经保护。使用这种方法的14-3-3θ过表达在MPTP给药三周后并未减少黑质中MPTP诱导的多巴胺能细胞损失，也未减少纹状体中多巴胺（DA）及其代谢产物的消耗。然而，与对照组相比，14-3-3θ过表达的小鼠在MPTP给药八周后纹状体DA代谢产物出现了较晚的部分恢复，这表明14-3-3θ过表达可能有助于存活的多巴胺能神经元的功能恢复。相反，我们研究了在表达泛14-3-3抑制剂双肽素的转基因小鼠中破坏14-3-3功能是否会加剧MPTP诱导的毒性。我们发现双肽素表达会促进MPTP处理后的多巴胺能细胞损失。总之，这些发现表明14-3-3θ过表达促进DA代谢产物的恢复，而14-3-3抑制会加剧MPTP诱导的PD小鼠模型中的神经元损失。
