Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR pathway as a therapeutic target in Friedreichs ataxia
Identifieur interne : 000E77 ( Istex/Corpus ); précédent : 000E76; suivant : 000E78Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR pathway as a therapeutic target in Friedreichs ataxia
Auteurs : Giovanni Coppola ; Daniele Marmolino ; Daning Lu ; Qing Wang ; Miriam Cnop ; Myriam Rai ; Fabio Acquaviva ; Sergio Cocozza ; Massimo Pandolfo ; Daniel H. GeschwindSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-07-01.
Abstract
Friedreichs ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPAR) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPAR coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPAR pathway affects frataxin levels in vitro, supporting PPAR as a novel therapeutic target in FRDA.
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DOI: 10.1093/hmg/ddp183
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Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPAR) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPAR coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPAR pathway affects frataxin levels in vitro, supporting PPAR as a novel therapeutic target in FRDA.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Giovanni Coppola</name><affiliations><json:string>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</json:string></affiliations></json:item><json:item><name>Daniele Marmolino</name><affiliations><json:string>Laboratoire de Neurologie Exprimentale</json:string></affiliations></json:item><json:item><name>Daning Lu</name><affiliations><json:string>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</json:string></affiliations></json:item><json:item><name>Qing Wang</name><affiliations><json:string>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</json:string></affiliations></json:item><json:item><name>Miriam Cnop</name><affiliations><json:string>Division of Endocrinology</json:string><json:string>Laboratory of Experimental Medicine, Hpital Erasme, Universit Libre de Bruxelles (ULB), 1070 Brussels, Belgium</json:string></affiliations></json:item><json:item><name>Myriam Rai</name><affiliations><json:string>Laboratoire de Neurologie Exprimentale</json:string></affiliations></json:item><json:item><name>Fabio Acquaviva</name><affiliations><json:string>Department of Cellular and Molecular Biology, University of Naples Federico II, IEOS CNR, Via Pansini 5, 80131 Naples, Italy</json:string></affiliations></json:item><json:item><name>Sergio Cocozza</name><affiliations><json:string>Department of Cellular and Molecular Biology, University of Naples Federico II, IEOS CNR, Via Pansini 5, 80131 Naples, Italy</json:string></affiliations></json:item><json:item><name>Massimo Pandolfo</name><affiliations><json:string>Laboratoire de Neurologie Exprimentale</json:string></affiliations></json:item><json:item><name>Daniel H. 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We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPAR) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPAR coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. 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type="first">Daniele</forename><surname>Marmolino</surname></persName><affiliation>Laboratoire de Neurologie Exprimentale</affiliation></author><author xml:id="author-3"><persName><forename type="first">Daning</forename><surname>Lu</surname></persName><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation></author><author xml:id="author-4"><persName><forename type="first">Qing</forename><surname>Wang</surname></persName><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation></author><author xml:id="author-5"><persName><forename type="first">Miriam</forename><surname>Cnop</surname></persName><affiliation>Division of Endocrinology</affiliation><affiliation>Laboratory of Experimental Medicine, Hpital Erasme, Universit Libre de Bruxelles (ULB), 1070 Brussels, Belgium</affiliation></author><author xml:id="author-6"><persName><forename type="first">Myriam</forename><surname>Rai</surname></persName><affiliation>Laboratoire de Neurologie Exprimentale</affiliation></author><author xml:id="author-7"><persName><forename type="first">Fabio</forename><surname>Acquaviva</surname></persName><affiliation>Department of Cellular and Molecular Biology, University of Naples Federico II, IEOS CNR, Via Pansini 5, 80131 Naples, Italy</affiliation></author><author xml:id="author-8"><persName><forename type="first">Sergio</forename><surname>Cocozza</surname></persName><affiliation>Department of Cellular and Molecular Biology, University of Naples Federico II, IEOS CNR, Via Pansini 5, 80131 Naples, Italy</affiliation></author><author xml:id="author-9"><persName><forename type="first">Massimo</forename><surname>Pandolfo</surname></persName><note type="biography">These authors co-directed this work.</note><affiliation>These authors co-directed this work.</affiliation><affiliation>Laboratoire de Neurologie Exprimentale</affiliation></author><author xml:id="author-10"><persName><forename type="first">Daniel H.</forename><surname>Geschwind</surname></persName><email>dhg@ucla.edu</email><note type="biography">These authors co-directed this work.</note><affiliation>These authors co-directed this work.</affiliation><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-07-01"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="2452">2452</biblScope><biblScope unit="page" to="2461">2461</biblScope></imprint></monogr><idno 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Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPAR) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPAR coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPAR pathway affects frataxin levels in vitro, supporting PPAR as a novel therapeutic target in FRDA.</p></abstract></profileDesc><revisionDesc><change when="2009-04-17">Created</change><change when="2009-07-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddp183</article-id><article-id pub-id-type="publisher-id">ddp183</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Coppola</surname><given-names>Giovanni</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Marmolino</surname><given-names>Daniele</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Daning</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Qing</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cnop</surname><given-names>Miriam</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Rai</surname><given-names>Myriam</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Acquaviva</surname><given-names>Fabio</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Cocozza</surname><given-names>Sergio</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Pandolfo</surname><given-names>Massimo</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="fn" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Geschwind</surname><given-names>Daniel H.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref><xref ref-type="fn" rid="FN1">†</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Program in Neurogenetics, Department of Neurology</addr-line>, <institution>David Geffen School of Medicine, University of California at Los Angeles</institution>, <addr-line>CA 90095</addr-line>, <country>USA</country></aff><aff id="af2"><label>2</label><addr-line>Laboratoire de Neurologie Expérimentale</addr-line></aff><aff id="af3"><label>3</label><addr-line>Division of Endocrinology</addr-line></aff><aff id="af4"><label>4</label><addr-line>Laboratory of Experimental Medicine</addr-line>, <institution>Hôpital Erasme, Université Libre de Bruxelles (ULB)</institution>, <addr-line>1070 Brussels</addr-line>, <country>Belgium</country></aff><aff id="af5"><label>5</label><addr-line>Department of Cellular and Molecular Biology</addr-line>, <institution>University of Naples ‘Federico II’</institution>, <addr-line>IEOS CNR, Via Pansini 5, 80131 Naples</addr-line>, <country>Italy</country></aff><author-notes><fn id="FN1"><label>†</label><p>These authors co-directed this work.</p></fn><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+1 3107946570</phone>; Fax: <fax>+1 3102672401</fax>; Email: <email>dhg@ucla.edu</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>7</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>17</day><month>4</month><year>2009</year></pub-date><volume>18</volume><issue>13</issue><fpage>2452</fpage><lpage>2461</lpage><history><date date-type="received"><day>26</day><month>2</month><year>2009</year></date><date date-type="accepted"><day>14</day><month>4</month><year>2009</year></date></history><copyright-statement>© 2009 The Author(s)</copyright-statement><copyright-year>2009</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>Friedreich’s ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARγ coactivator <italic>Pgc1a</italic> and transcription factor <italic>Srebp1</italic> in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARγ pathway affects frataxin levels <italic>in vitro</italic>, supporting PPARγ as a novel therapeutic target in FRDA.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR pathway as a therapeutic target in Friedreichs ataxia</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPAR pathway as a therapeutic target in Friedreichs ataxia</title></titleInfo><name type="personal"><namePart type="given">Giovanni</namePart><namePart type="family">Coppola</namePart><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniele</namePart><namePart type="family">Marmolino</namePart><affiliation>Laboratoire de Neurologie Exprimentale</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daning</namePart><namePart type="family">Lu</namePart><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Qing</namePart><namePart type="family">Wang</namePart><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Miriam</namePart><namePart type="family">Cnop</namePart><affiliation>Division of Endocrinology</affiliation><affiliation>Laboratory of Experimental Medicine, Hpital Erasme, Universit Libre de Bruxelles (ULB), 1070 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Myriam</namePart><namePart type="family">Rai</namePart><affiliation>Laboratoire de Neurologie Exprimentale</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fabio</namePart><namePart type="family">Acquaviva</namePart><affiliation>Department of Cellular and Molecular Biology, University of Naples Federico II, IEOS CNR, Via Pansini 5, 80131 Naples, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sergio</namePart><namePart type="family">Cocozza</namePart><affiliation>Department of Cellular and Molecular Biology, University of Naples Federico II, IEOS CNR, Via Pansini 5, 80131 Naples, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Massimo</namePart><namePart type="family">Pandolfo</namePart><affiliation>Laboratoire de Neurologie Exprimentale</affiliation><description>These authors co-directed this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel H.</namePart><namePart type="family">Geschwind</namePart><affiliation>Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA</affiliation><affiliation>E-mail: dhg@ucla.edu</affiliation><description>These authors co-directed this work.</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-07-01</dateIssued><dateCreated encoding="w3cdtf">2009-04-17</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Friedreichs ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPAR) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPAR coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPAR pathway affects frataxin levels in vitro, supporting PPAR as a novel therapeutic target in FRDA.</abstract><note type="footnotes">These authors co-directed this work.</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>13</number></detail><extent unit="pages"><start>2452</start><end>2461</end></extent></part></relatedItem><identifier type="istex">B0B807D1A40142A33E0B7283782140F6DC9FBADD</identifier><identifier type="DOI">10.1093/hmg/ddp183</identifier><identifier type="ArticleID">ddp183</identifier><accessCondition type="use and reproduction" contentType="copyright">2009 The Author(s)</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><original>true</original><mimetype>image/tiff</mimetype><extension>tiff</extension><uri>https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/covers/tiff</uri></json:item><json:item><original>true</original><mimetype>text/html</mimetype><extension>html</extension><uri>https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/covers/html</uri></json:item></covers><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/annexes/jpeg</uri></json:item><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/annexes/gif</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">GENETICS & HEREDITY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI><json:item><type>refBibs</type><uri>https://api.istex.fr/document/B0B807D1A40142A33E0B7283782140F6DC9FBADD/enrichments/refBibs</uri></json:item></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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