Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Jining Medical University Affiliated Hospital, Jining Medical University, Jining, Shandong 272029, China.
Neurosci Lett. 2013 Feb 8;534:193-8. doi: 10.1016/j.neulet.2012.12.039. Epub 2013 Jan 4.
Parkinson's disease (PD) is the second most common neurodegenerative disease. The majority of PD cases are sporadic, for which genetic causes and underlying molecular mechanisms remain largely unclear. Autophagy, a highly conserved cellular process that governs the breakdown of long-lived proteins and organelles, has been involved in the degradation of α-synuclein (α-Syn), the main component of Lewy bodies. Accumulating evidence implicates deregulation of autophagy in the development and progression of sporadic PD. Altered autophagic gene expression has been observed in the brain tissues from PD patients and animal models. We hypothesized that changes in expression levels of autophagy-related genes (ATGs), rather than mutations associated with amino acid changes, may contribute to PD onset. In this study, the ATG7 gene promoter was sequenced bi-directionally in groups of sporadic PD patients and ethnic-matched healthy controls. As predicted, four novel heterozygous variants, 11313449G>A, 11313811T>C, 11313913G>A and 11314041G>A, were identified in five PD patients, but in none of the controls, which significantly decreased transcriptional activities of the ATG7 gene promoter. Two novel heterozygous variants, 11312947G>A and 11313006C>G, were only found in controls, which did not affect transcriptional activities of the ATG7 gene promoter. The other five novel variants were found in PD patients and controls with similar frequencies. Taken together, the sequence variants within the ATG7 gene promoter identified in PD patients may change ATG7 protein levels, which in turn would influence autophagic activity, contributing to PD onset as a risk factor.
帕金森病（PD）是第二常见的神经退行性疾病。大多数 PD 病例为散发性，其遗传原因和潜在分子机制仍很大程度上不清楚。自噬是一种高度保守的细胞过程，负责长寿命蛋白质和细胞器的分解，已涉及α-突触核蛋白（α-Syn）的降解，α-Syn 是路易小体的主要成分。越来越多的证据表明，自噬的失调参与了散发性 PD 的发生和发展。在 PD 患者和动物模型的脑组织中观察到自噬基因表达的改变。我们假设自噬相关基因（ATGs）的表达水平的变化，而不是与氨基酸变化相关的突变，可能导致 PD 的发生。在这项研究中，我们在散发性 PD 患者和种族匹配的健康对照组中双向测序了 ATG7 基因启动子。正如预测的那样，在五名 PD 患者中发现了四个新的杂合变体，11313449G>A、11313811T>C、11313913G>A 和 11314041G>A，但在对照组中没有发现，这显著降低了 ATG7 基因启动子的转录活性。两个新的杂合变体，11312947G>A 和 11313006C>G，仅在对照组中发现，它们不影响 ATG7 基因启动子的转录活性。其他五个新变体在 PD 患者和对照组中以相似的频率发现。总之，在 PD 患者中鉴定的 ATG7 基因启动子内的序列变体可能改变 ATG7 蛋白水平，进而影响自噬活性，作为一个风险因素导致 PD 的发生。
