Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2013;8(2):e56092. doi: 10.1371/journal.pone.0056092. Epub 2013 Feb 7.
The angiogenic factor, angiogenin, has been recently linked to both Amyotrophic Lateral Sclerosis (ALS) and Parkinson Disease (PD). We have recently shown that endogenous angiogenin levels are dramatically reduced in an alpha-synuclein mouse model of PD and that exogenous angiogenin protects against cell loss in neurotoxin-based cellular models of PD. Here, we extend our studies to examine whether activation of the prosurvival Akt pathway is required for angiogenin's neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+), as observed in ALS models, and to test the effect of virally-mediated overexpression of angiogenin in an in vivo PD model. Using a dominant negative Akt construct, we demonstrate that inhibition of the Akt pathway does not reduce the protective effect of angiogenin against MPP+ toxicity in the dopaminergic SH-SY5Y cell line. Furthermore, an ALS-associated mutant of angiogenin, K40I, which fails to induce Akt phosphorylation, was similar to wildtype angiogenin in protection against MPP+. These results confirm previous work showing neuroprotective effects of angiogenin against MPP+, and indicate that Akt is not required for this protective effect. We also investigated whether adeno-associated viral serotype 2 (AAV2)-mediated overexpression of angiogenin protects against dopaminergic neuron loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. We found that angiogenin overexpression using this approach does not reduce the MPTP-induced degeneration of dopaminergic cells in the substantia nigra, nor limit the depletion of dopamine and its metabolites in the striatum. Together, these findings extend the evidence for protective effects of angiogenin in vitro, but also suggest that further study of in vivo models is required to translate these effects into meaningful therapies.
血管生成因子血管生成素最近与肌萎缩侧索硬化症（ALS）和帕金森病（PD）都有关联。我们最近的研究表明，在α-突触核蛋白 PD 小鼠模型中，内源性血管生成素水平显著降低，而外源性血管生成素可防止神经毒素诱导的 PD 细胞模型中的细胞损失。在此，我们进一步研究了血管生成素的神经保护作用是否需要激活生存素 Akt 途径来抵抗在 ALS 模型中观察到的 1-甲基-4-苯基吡啶（MPP+），以及检测病毒介导的血管生成素在体内 PD 模型中的过表达的效果。使用显性失活 Akt 构建体，我们证明 Akt 途径的抑制不会降低血管生成素对多巴胺能 SH-SY5Y 细胞系中 MPP+毒性的保护作用。此外，与野生型血管生成素相似，不能诱导 Akt 磷酸化的 ALS 相关突变型血管生成素 K40I 在抵抗 MPP+方面也具有保护作用。这些结果证实了先前的研究工作，表明血管生成素对 MPP+具有神经保护作用，并且表明 Akt 不是这种保护作用所必需的。我们还研究了腺相关病毒血清型 2（AAV2）介导的血管生成素过表达是否可以防止 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中多巴胺能神经元的丢失。我们发现，通过这种方法过表达血管生成素并不能减轻 MPTP 诱导的黑质多巴胺能细胞的变性，也不能限制纹状体中多巴胺及其代谢物的耗竭。这些发现不仅扩展了血管生成素在体外具有保护作用的证据，而且还表明需要进一步研究体内模型，才能将这些作用转化为有意义的治疗方法。
