GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein
GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein
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DOI：
10.1073/pnas.0802437105
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发表时间：
2008-08-05
影响因子：
11.1
通讯作者：
Schlossmacher, Michael G.
中科院分区：
文献类型：
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作者：
Scherzer, Clemens R.;Grass, Jeffrey A.;Schlossmacher, Michael G.
基因座增殖导致α -突触核蛋白基因（SNCA）剂量增加可导致常染色体显性帕金森病（PD）。SNCA表达的变异可能是常见的、遗传复杂的PD的关键，但潜在的调节机制尚不清楚。我们发现SNCA和血红素代谢基因ALAS2、FECH和BLVRB在113份人类血液样本中形成一个紧密相关的基因表达块，其中SNCA自然丰富（验证P = 1.6 × 10（-11）、1.8 × 10（-10）和6.6 × 10(-5)）。遗传互补分析表明，这四个基因是由转录因子GATA-1共同诱导的。GATA-1特异性占据SNCA内含子-1内的一个保守区域，并直接诱导α -突触核蛋白增加6.9倍。内源性GATA-2在PD易感的大量黑质中高表达，占据内含子-1，并调节多巴胺能细胞中SNCA的表达。GATA因子和SNCA之间的这种关键联系可能使设计降低α -突触核蛋白产生的疗法成为可能。
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 substantial 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.