| Autor: |
Scherzer, Clemens R., Grass, Jeffrey A., Zhixiang Liao, Pepivani, Imelda, Bin Zheng, Eklund, Aron C., Neym, Paul A., Ng, Juliana, McGoldrick, Meghan, Mollenhauer, Brit, Bresnick, Emery H., Schlossmacher, Michael G. |
| Předmět: |
|
| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 8/5/2008, Vol. 105 Issue 31, p10907-10912, 6p, 5 Diagrams |
| Abstrakt: |
Increased α-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 BL VRB form a block of tightly correlated gene expression in 113 samples of human blood, where SNCA naturally abounds (validated P = 1.6 × 10-11, 1.8 × 10-10, and 6.6 × 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 α-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 α-synuclein production. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
