Scherzer Clemens R, Grass Jeffrey A, Liao Zhixiang, Pepivani Imelda, Zheng Bin, Eklund Aron C, Ney Paul A, Ng Juliana, McGoldrick Meghan, Mollenhauer Brit, Bresnick Emery H, Schlossmacher Michael G
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10907-12. doi: 10.1073/pnas.0802437105. Epub 2008 Jul 31.
Increased alpha-synuclein gene (SNCA) dosage due to locus multiplication causes autosomal dominant Parkinson's disease (PD). Variation in SNCA expression may be critical in common, genetically complex PD but the underlying regulatory mechanism is unknown. We show that SNCA and the heme metabolism genes ALAS2, FECH, and BLVRB form a block of tightly correlated gene expression in 113 samples of human blood, where SNCA naturally abounds (validated P = 1.6 x 10(-11), 1.8 x 10(-10), and 6.6 x 10(-5)). Genetic complementation analysis revealed that these four genes are co-induced by the transcription factor GATA-1. GATA-1 specifically occupies a conserved region within SNCA intron-1 and directly induces a 6.9-fold increase in alpha-synuclein. Endogenous GATA-2 is highly expressed in substantia nigra vulnerable to PD, occupies intron-1, and modulates SNCA expression in dopaminergic cells. This critical link between GATA factors and SNCA may enable therapies designed to lower alpha-synuclein production.
由于基因座倍增导致的α-突触核蛋白基因（SNCA）剂量增加会引发常染色体显性帕金森病（PD）。在常见的、遗传复杂的帕金森病中，SNCA表达的变化可能至关重要，但其潜在的调控机制尚不清楚。我们发现，在113份富含SNCA的人类血液样本中，SNCA与血红素代谢基因ALAS2、FECH和BLVRB形成了一组紧密相关的基因表达（验证后的P值分别为1.6×10⁻¹¹、1.8×10⁻¹⁰和6.6×10⁻⁵）。遗传互补分析表明，这四个基因由转录因子GATA-1共同诱导。GATA-1特异性占据SNCA内含子-1内的一个保守区域，并直接使α-突触核蛋白增加6.9倍。内源性GATA-2在易患帕金森病的黑质中高度表达，占据内含子-1，并调节多巴胺能细胞中SNCA的表达。GATA因子与SNCA之间的这一关键联系可能有助于设计降低α-突触核蛋白产生的治疗方法。
