GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein | Zendy

Clemens R. Scherzer | Zendy; Jeffrey A. Grass | Zendy; Zhixiang Liao | Zendy; Imelda Pepivani | Zendy; Bin Zheng | Zendy; Aron C. Eklund | Zendy; Paul A. Ney | Zendy; Juliag | Zendy; Meghan McGoldrick | Zendy; Brit Mollenhauer | Zendy; Emery H. Bresnick | Zendy; Michael G. Schlossmacher | Zendy

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GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein

Author(s) -

Clemens R. Scherzer,

Jeffrey A. Grass,

Zhixiang Liao,

Imelda Pepivani,

Bin Zheng,

Aron C. Eklund,

Paul A. Ney,

Juliag,

Meghan McGoldrick,

Brit Mollenhauer,

Emery H. Bresnick,

Michael G. Schlossmacher

Publication year - 2008

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.0802437105

Subject(s) - alpha synuclein , biology , substantia nigra , gene , transcription factor , genetics , gata transcription factor , gene expression , parkinson's disease , intron , microbiology and biotechnology , promoter , dopaminergic , disease , dopamine , medicine , endocrinology

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.

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