Department of Neurology, San Gerardo Hospital, Monza, Italy.
Parkinsonism Relat Disord. 2011 Nov;17(9):701-4. doi: 10.1016/j.parkreldis.2011.06.022. Epub 2011 Jul 20.
Alpha-synuclein accumulation in intracellular inclusions, oxidative stress and microglia-mediated inflammation in the substantia nigra are crucial events in the pathogenesis of Parkinson's disease (PD). Poly (ADP-ribose) polymerase-1 (PARP1), a DNA-binding enzyme and transcriptional regulator, plays an important role in modulating the cellular response to oxidative stress, inflammatory stimuli, and in apoptotic cell death. Inhibition of PARP1 results in significant neuroprotection in PD animal models; moreover PARP1 has a physiological role in the regulation of alpha-synuclein expression. A previous study had demonstrated that variants located within the PARP1 gene promoter reduce the risk of PD and delay the disease age at onset. In light of these data, we carried out an association study to investigate whether variability within this gene is associated with PD risk and disease age at onset in an Italian cohort composed of 600 PD patients and 592 healthy controls. To this purpose, we used a comprehensive tag SNP approach spanning the entire gene and the upstream and downstream regions. We did not detect any significant association of the PARP1 gene with PD either at genotypic or haplotypic level; none of the 11 genotyped SNPs was significantly associated with PD age at onset. We conclude that, despite previous evidence, PARP1 is not a susceptibility gene for PD in our population.
α-突触核蛋白在细胞内包涵体内的积累、氧化应激以及黑质中小胶质细胞介导的炎症，是帕金森病（PD）发病机制中的关键事件。多聚（ADP-核糖）聚合酶 1（PARP1）是一种 DNA 结合酶和转录调节因子，在调节细胞对氧化应激、炎症刺激和细胞凋亡的反应中发挥重要作用。PARP1 的抑制可导致 PD 动物模型中的显著神经保护作用；此外，PARP1 在调节α-突触核蛋白表达方面具有生理作用。先前的研究表明，位于 PARP1 基因启动子内的变异可降低 PD 的风险并延迟疾病发病年龄。有鉴于此，我们进行了一项关联研究，以调查该基因内的变异性是否与意大利队列中 600 名 PD 患者和 592 名健康对照者的 PD 风险和发病年龄相关。为此，我们使用了一种全面的标签 SNP 方法，涵盖了整个基因及其上下游区域。我们没有发现 PARP1 基因与 PD 在基因型或单倍型水平上存在任何显著关联；11 个已分型的 SNP 均与 PD 的发病年龄无显著关联。我们的结论是，尽管有先前的证据，但 PARP1 不是我们人群中 PD 的易感基因。
