GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein
Identifieur interne : 000651 ( Pmc/Curation ); précédent : 000650; suivant : 000652GATA 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.
Abstract
Increased α-synuclein gene (
Url:
DOI: 10.1073/pnas.0802437105
PubMed: 18669654
PubMed Central: 2504800
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Scherzer</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Grass, Jeffrey A" sort="Grass, Jeffrey A" uniqKey="Grass J" first="Jeffrey A." last="Grass">Jeffrey A. Grass</name><affiliation wicri:level="2"><nlm:aff id="aff2">Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison</wicri:cityArea></affiliation></author><author><name sortKey="Liao, Zhixiang" sort="Liao, Zhixiang" uniqKey="Liao Z" first="Zhixiang" last="Liao">Zhixiang Liao</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Pepivani, Imelda" sort="Pepivani, Imelda" uniqKey="Pepivani I" first="Imelda" last="Pepivani">Imelda Pepivani</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Zheng, Bin" sort="Zheng, Bin" uniqKey="Zheng B" first="Bin" last="Zheng">Bin Zheng</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Eklund, Aron C" sort="Eklund, Aron C" uniqKey="Eklund A" first="Aron C." last="Eklund">Aron C. Eklund</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Ney, Paul A" sort="Ney, Paul A" uniqKey="Ney P" first="Paul A." last="Ney">Paul A. Ney</name><affiliation wicri:level="2"><nlm:aff wicri:cut="; and" id="aff3">Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Department of Biochemistry, St. Jude Children's Research Hospital, Memphis</wicri:cityArea></affiliation></author><author><name sortKey="Ng, Juliana" sort="Ng, Juliana" uniqKey="Ng J" first="Juliana" last="Ng">Juliana Ng</name><affiliation wicri:level="1"><nlm:aff id="aff4">Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5</nlm:aff><country>Canada</country><wicri:regionArea>Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON</wicri:regionArea></affiliation></author><author><name sortKey="Mcgoldrick, Meghan" sort="Mcgoldrick, Meghan" uniqKey="Mcgoldrick M" first="Meghan" last="Mcgoldrick">Meghan Mcgoldrick</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Mollenhauer, Brit" sort="Mollenhauer, Brit" uniqKey="Mollenhauer B" first="Brit" last="Mollenhauer">Brit Mollenhauer</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Bresnick, Emery H" sort="Bresnick, Emery H" uniqKey="Bresnick E" first="Emery H." last="Bresnick">Emery H. Bresnick</name><affiliation wicri:level="2"><nlm:aff id="aff2">Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Wisconsin</region></placeName><wicri:cityArea>Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison</wicri:cityArea></affiliation></author><author><name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name><affiliation wicri:level="2"><nlm:aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge</wicri:cityArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5</nlm:aff><country>Canada</country><wicri:regionArea>Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON</wicri:regionArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18669654</article-id><article-id pub-id-type="pmc">2504800</article-id><article-id pub-id-type="publisher-id">4090</article-id><article-id pub-id-type="doi">10.1073/pnas.0802437105</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Medical Sciences</subject></subj-group></subj-group></article-categories><title-group><article-title>GATA transcription factors directly regulate the Parkinson's disease-linked gene α-synuclein</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Scherzer</surname><given-names>Clemens R.</given-names></name><xref ref-type="aff" rid="aff1">*</xref><xref ref-type="corresp" rid="cor1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN1"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Grass</surname><given-names>Jeffrey A.</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liao</surname><given-names>Zhixiang</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Pepivani</surname><given-names>Imelda</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Bin</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Eklund</surname><given-names>Aron C.</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Ney</surname><given-names>Paul A.</given-names></name><xref ref-type="aff" rid="aff3"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ng</surname><given-names>Juliana</given-names></name><xref ref-type="aff" rid="aff4"><sup>‖</sup></xref></contrib><contrib contrib-type="author"><name><surname>McGoldrick</surname><given-names>Meghan</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Mollenhauer</surname><given-names>Brit</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Bresnick</surname><given-names>Emery H.</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref><xref ref-type="corresp" rid="cor2">**</xref><xref ref-type="author-notes" rid="FN1"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schlossmacher</surname><given-names>Michael G.</given-names></name><xref ref-type="aff" rid="aff1">*</xref><xref ref-type="aff" rid="aff4"><sup>‖</sup></xref><xref ref-type="corresp" rid="cor3"><sup>††</sup></xref><xref ref-type="author-notes" rid="FN1"><sup>†</sup></xref></contrib><aff id="aff1">*Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139;</aff><aff id="aff2"><sup>§</sup>Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706;</aff><aff id="aff3"><sup>¶</sup>Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105; and</aff><aff id="aff4"><sup>‖</sup>Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5</aff></contrib-group><author-notes><corresp id="cor1"><sup>‡</sup>To whom correspondence may be addressed at: <addr-line>Laboratory for Neurogenomics, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 65 Landsdowne Street, Suite 307A, Cambridge, MA 02139.</addr-line> E-mail: <email>cscherzer@rics.bwh.harvard.edu</email></corresp><corresp id="cor2">**To whom correspondence may be addressed at: <addr-line>University of Wisconsin School of Medicine and Public Health, 383 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706.</addr-line> E-mail: <email>ehbresni@wisc.edu</email></corresp><corresp id="cor3"><sup>††</sup>To whom correspondence may be addressed at: <addr-line>Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road #1462, Ottawa, ON, Canada K1H 8M5.</addr-line> E-mail: <email>mschlossmacher@ohri.ca</email></corresp><fn fn-type="edited-by"><p>Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved May 27, 2008</p></fn><fn fn-type="con"><p>Author contributions: C.R.S., E.H.B., and M.G.S. designed research; C.R.S., J.A.G., Z.L., I.P., B.Z., A.C.E., P.A.N., J.N., M.M., B.M., E.H.B., and M.G.S. performed research; C.R.S., B.Z., and A.C.E. contributed new reagents/analytic tools; C.R.S., J.A.G., Z.L., I.P., B.Z., A.C.E., P.A.N., J.N., E.H.B., and M.G.S. analyzed data; and C.R.S., E.H.B., and M.G.S. wrote the paper.</p></fn><fn id="FN1" fn-type="equal"><p><sup>†</sup>C.R.S., E.H.B., and M.G.S. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>5</day><month>8</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>31</day><month>7</month><year>2008</year></pub-date><volume>105</volume><issue>31</issue><fpage>10907</fpage><lpage>10912</lpage><history><date date-type="received"><day>13</day><month>3</month><year>2008</year></date></history><permissions><copyright-statement>© 2008 by The National Academy of Sciences of the USA</copyright-statement></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zpq03108010907.pdf"></self-uri><abstract><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></abstract><kwd-group><kwd>α-synuclein dosage</kwd><kwd>GATA-1</kwd><kwd>GATA-2</kwd><kwd>gene expression</kwd><kwd>microarray</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:18669654" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \
| NlmPubMed2Wicri -a ParkinsonCanadaV1
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