GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein
CR Scherzer, JA Grass, Z Liao… - Proceedings of the …, 2008 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2008•National Acad Sciences
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 BLVRB 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 …
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× 10− 11, 1.8× 10− 10, and 6.6× 10− 5). Genetic complementation …
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 BLVRB 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.
National Acad Sciences