GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein.
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.
Scherzer
Clemens R
CR
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA. cscherzer@rics.bwh.harvard.edu
Grass
Jeffrey A
JA
Liao
Zhixiang
Z
Pepivani
Imelda
I
Zheng
Bin
B
Eklund
Aron C
AC
Ney
Paul A
PA
Ng
Juliana
J
McGoldrick
Meghan
M
Mollenhauer
Brit
B
Bresnick
Emery H
EH
Schlossmacher
Michael G
MG
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*
D050980:GATA Transcription Factors; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human