LRRK2基因G2019S突变帕金森病相关基因的生物信息学分析

doi:10.16098/j.issn.0529-1356.2015.03.003

解剖学报 ›› 2015 ›› Issue (3) : 304-309. DOI: 10.16098/j.issn.0529-1356.2015.03.003

神经生物学

LRRK2基因G2019S突变帕金森病相关基因的生物信息学分析

陈光乐郑文岭马文丽*

作者信息 +

Bioinformatics analysis of genes related to Parkinson’s disease with LRRK2 (G2019S) mutation

CHEN Guang-le ZHENG Wen-ling MA Wen-li*

Author information +

文章历史 +

摘要

目的从分子水平揭示富亮氨酸重复激酶2（LRRK2)基因G2019S突变帕金森病的发病机制，为临床诊断及治疗提供新思路。方法在公共基因芯片数据库（GEO）中下载LRRK2基因G2019S突变帕金森病的相关基因芯片数据（GSE22491），其中LRRK2(G2019S)突变帕金森病样本10 例，正常控制组样本8 例，利用Qlucore Omics Explorer（QOE）3.0 软件、DAVID、STRING等在线分析软件对LRRK2基因G2019S突变帕金森病差异基因进行生物信息学分析。结果 QOE3.0分析筛选出1752个LRRK2基因G2019S突变帕金森病差异基因，其中上调191个，下调1561个。对其进行生物信息学分析发现，SKP2、RBX1、SKP1、CUL1、CUL4A 等基因以及核糖体信号通路、氧化磷酸化信号通路、蛋白酶体信号通路、白细胞跨内皮迁移信号通路、磷酸戊糖途径信号通路、枸橼酸信号通路、Fcγ受体（FcγR）介导的吞噬通路等在LRRK2基因G2019S突变帕金森病的发生发展中可能起着重要作用。结论通过生物信息学分析LRRK2基因G2019S突变帕金森病相关基因芯片数据，提示LRRK2基因G2019S突变帕金森病发病是多种基因、多种分子机制相互作用的结果，对相关分子机制的进一步分析有利于揭示LRRK2基因G2019S突变帕金森病的发病机制。

Abstract

Objective To investigate the genes from Parkinson’s disease (PD) patients carrying the mutation of leucine-rich repeat kinase 2(LRRK2) gene（G2019S）and explore the molecular mechanism of Parkinson’s disease. Methods Microarray dataset GSE22491 from the Gene Expression Omnibus database, the dataset includes 10 PD and 8 control samples, and analyzed by bioinformatics methods using Qlucore Omics Explorer（QOE）3.0，DAVID and String. Results A total of 1752 genes were identified as differentially expressed genes, of which 191 were upregulated and 1561 were downregulated in PD. The main biological pathways involved included ribosome,oxidative phosphorylation, proteasome, Leukocyte transendothelial migration, pentose phosphate pathway, citrate cycle, Fc gamma R-mediated phagocytosis and genes of SKP2、RBX1、SKP1、CUL1、CUL4A etc may plays important roles in the molecular mechanism of Parkinson’s disease. Conclusion The pathogenesis of PD involves multiple genes, and investigations of these genes may provide valuable insights into the mechanism of PD with mutation of LRRK2 gene (G2019).

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用

陈光乐郑文岭马文丽*. LRRK2基因G2019S突变帕金森病相关基因的生物信息学分析[J]. 解剖学报. 2015(3): 304-309 https://doi.org/10.16098/j.issn.0529-1356.2015.03.003

CHEN Guang-le ZHENG Wen-ling MA Wen-li*. Bioinformatics analysis of genes related to Parkinson’s disease with LRRK2 (G2019S) mutation[J]. Acta Anatomica Sinica. 2015(3): 304-309 https://doi.org/10.16098/j.issn.0529-1356.2015.03.003

参考文献

［1］Halliday GM, McCann H. The progression of pathology in Parkinson’S disease［J］. Ann N Y Acad Sci, 2010, 1184(2):188-195.
［2］Yao N, Xu QY. The locus coeruleus pathology and its role in the pathogenesis of Parkinsons disease ［J］.Acta Anatomica Sinica，2014, 45(2):291-296.(in Chinese)
姚宁，徐群渊. 蓝斑核在帕金森病发病中的病理改变及其作用［J］. 解剖学报，2014，45 (2)：291-296.
［3］Breit S, Wachter L, Schmid-Bielenberg D, et al. Efective long-term subthalamic stimulation in PARK8 positive Parkinson’s disease［J］. J Neurol, 2010, 257(7):1205-1207.
［4］Clark LN, Wang Y, Karlins E, et al. Frequency of LRRK2 mutations in early-and late-onset Parkinson disease［J］. Neurology, 2006, 67(10):1786-1791.
［5］Di Fonzo A, Rohé CF, Ferreira J, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease［J］. Lancet, 2005, 365(9457):412-415.
［6］Zabetian CP, Samii A, Mosley AD, et al. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations［J］. Neurology, 2005, 65(5):741-744.
［7］Aasly JO, Toft M, Fernandez-Mata I, et al. Clinical features of LRRK2-associated Parkinson’s disease in central Norway［J］. Ann Neurol, 2005, 57(5):762-765.
［8］Ishihara L, Warren L, Gibson R,et al. Clinical features of Parkinson disease with homozygous leucine-rich repeat kinase 2 G2019S mutations［J］. Arch Neurol, 2006, 63(9):1250-1254.
［9］Grunblatt E, Mandel S, Jacob-Hirsch J，et al. Gene expression profiling of parkinsonian substan-tia nigra pars compacta;alterations in ubiquitine-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhe- sion/cellular matrix and vesicle trafficking genes［J］. Neural Transm, 2004,111 (12)：1543-1573.
［10］Zhang Y, James M, Middleton FA，et al. Transcriptional analysis of multiple brain regions in Parkinson’s disease supports the involvement of specific protein processing, energy metabolism and sig- nalling pathways, and suggests novel disease mechanisms. ［J］.Am J Med Genet B Neuropsychiatr Genet, 2005,137B (1)：5-16.
［11］Miller RM, Kiser GL, Kaysser TM，et al. Robust deregulation of gene expression in substantia nigra and striatum in Parkinson’s disease［J］. Neurobiol Dis，2006, 21 (2)：305-313.
［12］Li CF, Wang JM, Kang HY, et al. Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma: potential implications in tumor progression and therapeutics［J］. Clin Cancer Res，2012, 18(6):1598-1610.
［13］Drobnjak M, Melamed J, Taneja S, et al. Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients［J］. Clin Cancer Res，2003, 9(7):2613-2619. 
［14］Gstaiger M, Jordan R, Lim M, et al. Skp2 is oncogenic and overexpressed in human cancers［J］. Proc Natl Acad Sci USA, 2001, 98(9):5043-5048. 
［15］Li BL, Lu W, Yang Q, et al. Skp2 regulates receptor through ubiquitin-mediated degradation independent ofAkt/mTOR pathways in prostate cancer［J］. Prostate, 2014, 74(4):421-432.
［16］Migita K, Takayama T, Matsumoto S, et al. Prognostic impact of RING box protein-1 (RBX1) expression in gastric cancer［J］. Gastric Cancer, 2014, 17(4):601-609.
［17］Kanatsu-Shinohara M, Onoyama L, Nakayama KI, et al. Skp1-Cullin-F-box(SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal［J］. Proc Natl Acad Sci USA, 2014, 111(24):8826-8831.
［18］Fan YC, Zhu YS, Mei PJ, et al. Cullin1 regulates proliferation, migration and invasion of glioma cells［J］. Med Oncol, 2014, 31(10):227.
［19］Nag AS, Baqchi S, Raychaudhuri P. Cul4A physically associates with MDM2 and participates in the proteolysis of p53［J］.Cancer Res, 2004, 64(22):8152-8155.
［20］Saucedo-Cuevas LP, Ruppen I, Ximénez-Embún P, et al. CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response［J］. Oncotarget, 2014, 5(8):2330-2343.