GATA Transcription Factors Directly Regulate the Parkinson's Disease-linked Gene Alpha-synuclein

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Aug 2

PMID 18669654

Citations 147

Authors

Clemens R Scherzer

Jeffrey A Grass

Zhixiang Liao

Imelda Pepivani

Bin Zheng

Aron C Eklund

Paul A Ney

Juliana Ng

Meghan McGoldrick

Brit Mollenhauer

Emery H Bresnick

Michael G Schlossmacher

Affiliations

Soon will be listed here.

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.

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