title: GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein.
abstract: 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.
authors.affiliation: Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA. cscherzer@rics.bwh.harvard.edu
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Grass
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Liao
authors.forename: Imelda
authors.initials: I
authors.lastname: Pepivani
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ney
authors.forename: Juliana
authors.initials: J
authors.lastname: Ng
authors.forename: Meghan
authors.initials: M
authors.lastname: McGoldrick
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D019295:Computational Biology; D004797:Enzyme-Linked Immunosorbent Assay; D050980:GATA Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005816:Genetic Complementation Test; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D046228:Microarray Analysis; D010300:Parkinson Disease / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D050980:GATA Transcription Factors; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human