Li Yuequn, Huang Jian, Pang Shuchao, Wang Haihua, Zhang Aimei, Hawley Robert G, Yan Bo
Division of Transcranial Doppler Ultrasound, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China.
Shandong Provincial Sino-US Cooperation Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272029, China.
Neurosci Lett. 2017 Mar 16;643:22-26. doi: 10.1016/j.neulet.2017.02.028. Epub 2017 Feb 13.
Parkinson's disease (PD) is a common and progressive neurodegenerative disease, including familial and sporadic cases. To date, genetic causes for sporadic PD, majority of PD cases, remain largely unknown. Accumulating evidence indicates that dysfunctional autophagy, a highly conserved cellular process, is involved in the PD pathogenesis. We speculated that changed expression levels of autophagy-related genes (ATG) may contribute to PD development. Previously, we have genetically analyzed ATG5 and ATG7 genes in sporadic PD patients and identified several functional DNA sequence variants (DSVs). In groups of sporadic PD patients and ethic-matched healthy controls in this study, we further genetically and functionally analyzed the promoter of ATG12, a critical gene for autophagososme formation. The results showed that three DNA sequence variants (DSVs), g.115842507G>T,g.115842394C>T and g.115841817_18del, were identified three PD patients, which significantly altered transcriptional activity of ATG12 gene promoter, probably due to abolishing or creating binding sites for transcription factors. The transcriptional activity of ATG12 gene promoter was not significantly affected by other two DSVs identified in PD patients, g.115842640A>C and g.115842242G>C, which may not alter binding sites for transcription factors. Therefore, these three functional DSVs identified in PD patient may change ATG12 protein levels, contributing to PD development as a risk factor by interfering with autophagy as well as non-autophagy functions.
帕金森病（PD）是一种常见的进行性神经退行性疾病，包括家族性和散发性病例。迄今为止，散发性PD（大多数PD病例）的遗传病因在很大程度上仍不清楚。越来越多的证据表明，自噬功能障碍这一高度保守的细胞过程参与了PD的发病机制。我们推测自噬相关基因（ATG）表达水平的改变可能有助于PD的发展。此前，我们对散发性PD患者的ATG5和ATG7基因进行了遗传分析，并鉴定出了几种功能性DNA序列变异（DSV）。在本研究的散发性PD患者组和种族匹配的健康对照组中，我们进一步对自噬体形成的关键基因ATG12的启动子进行了遗传和功能分析。结果显示，在3例PD患者中鉴定出3个DNA序列变异（DSV），即g.115842507G>T、g.115842394C>T和g.115841817_18del，它们显著改变了ATG12基因启动子的转录活性，这可能是由于消除或产生了转录因子的结合位点。PD患者中鉴定出的另外两个DSV，即g.115842640A>C和g.115842242G>C，对ATG12基因启动子的转录活性没有显著影响，这可能不会改变转录因子的结合位点。因此，在PD患者中鉴定出的这三个功能性DSV可能会改变ATG12蛋白水平，通过干扰自噬以及非自噬功能作为危险因素促进PD的发展。
