ParkinsonCanadaV1, Main, Exploration, bibRecord, 002191

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

Identifieur interne : 002191 ( Main/Exploration ); précédent : 002190; suivant : 002192

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

Auteurs : Clemens R. Scherzer [États-Unis] ; Jeffrey A. Grass [États-Unis] ; Zhixiang Liao [États-Unis] ; Imelda Pepivani [États-Unis] ; Bin Zheng [États-Unis] ; Aron C. Eklund [États-Unis] ; Paul A. Ney [États-Unis] ; Juliana Ng [Canada] ; Meghan Mcgoldrick [États-Unis] ; Brit Mollenhauer [États-Unis] ; Emery H. Bresnick [États-Unis] ; Michael G. Schlossmacher [États-Unis, Canada]

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2008.

RBID : PMC:2504800

Abstract

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504800

DOI: 10.1073/pnas.0802437105
PubMed: 18669654
PubMed Central: 2504800

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en"><p>Increased α-synuclein gene (<italic>SNCA</italic>
) dosage due to locus multiplication causes autosomal dominant Parkinson's disease (PD). Variation in <italic>SNCA</italic>
 expression may be critical in common, genetically complex PD but the underlying regulatory mechanism is unknown. We show that <italic>SNCA</italic>
 and the heme metabolism genes <italic>ALAS2</italic>
, <italic>FECH</italic>
, and <italic>BLVRB</italic>
 form a block of tightly correlated gene expression in 113 samples of human blood, where <italic>SNCA</italic>
 naturally abounds (validated <italic>P</italic>
 = 1.6 × 10<sup>−11</sup>
, 1.8 × 10<sup>−10</sup>
, and 6.6 × 10<sup>−5</sup>
). 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 <italic>SNCA</italic>
 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 <italic>SNCA</italic>
 expression in dopaminergic cells. This critical link between GATA factors and <italic>SNCA</italic>
 may enable therapies designed to lower α-synuclein production.</p>
</div>
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<name sortKey="Bresnick, Emery H" sort="Bresnick, Emery H" uniqKey="Bresnick E" first="Emery H." last="Bresnick">Emery H. Bresnick</name>
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<name sortKey="Grass, Jeffrey A" sort="Grass, Jeffrey A" uniqKey="Grass J" first="Jeffrey A." last="Grass">Jeffrey A. Grass</name>
<name sortKey="Liao, Zhixiang" sort="Liao, Zhixiang" uniqKey="Liao Z" first="Zhixiang" last="Liao">Zhixiang Liao</name>
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<name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name>
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<country name="Canada"><noRegion><name sortKey="Ng, Juliana" sort="Ng, Juliana" uniqKey="Ng J" first="Juliana" last="Ng">Juliana Ng</name>
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La maladie de Parkinson au Canada (serveur d'exploration)

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

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

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