Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment
Identifieur interne : 001A01 ( Istex/Corpus ); précédent : 001A00; suivant : 001A02Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment
Auteurs : Wei Song ; Hillel Zukor ; Shih-Hsiung Lin ; Adrienne Liberman ; Ayda Tavitian ; Jeannie Mui ; Hojatollah Vali ; Carine Fillebeen ; Kostas Pantopoulos ; Ting-Di Wu ; Jean-Luc Guerquin-Kern ; Hyman M. SchipperSource :
- Journal of Neurochemistry [ 0022-3042 ] ; 2012-10.
Abstract
The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian CNS remain poorly understood. The stress protein, HO‐1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and CO and is up‐regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. HO‐1 induction in primary astroglial cultures promotes deposition of non‐transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial HO‐1 in vivo, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional GFAP.HMOX1 transgenic mice that selectively over‐express human HO‐1 in the astrocytic compartment. At 48 weeks, the GFAP.HMOX1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron‐regulatory and iron‐binding proteins relative to age‐matched wild‐type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO− signals in the transgenic, but not wild‐type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by TEM. Sustained up‐regulation of HO‐1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease‐affected neural tissues. Curtailment of glial HO‐1 hyperactivity may limit iron‐mediated cytotoxicity in aging and degenerating neural tissues.
Url:
DOI: 10.1111/j.1471-4159.2012.07914.x
Links to Exploration step
ISTEX:F0D5E4339A4E31F36CA2940BEFAE38B0561B7008Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title><author><name sortKey="Song, Wei" sort="Song, Wei" uniqKey="Song W" first="Wei" last="Song">Wei Song</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Zukor, Hillel" sort="Zukor, Hillel" uniqKey="Zukor H" first="Hillel" last="Zukor">Hillel Zukor</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Lin, Shih Siung" sort="Lin, Shih Siung" uniqKey="Lin S" first="Shih-Hsiung" last="Lin">Shih-Hsiung Lin</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Liberman, Adrienne" sort="Liberman, Adrienne" uniqKey="Liberman A" first="Adrienne" last="Liberman">Adrienne Liberman</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Tavitian, Ayda" sort="Tavitian, Ayda" uniqKey="Tavitian A" first="Ayda" last="Tavitian">Ayda Tavitian</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Mui, Jeannie" sort="Mui, Jeannie" uniqKey="Mui J" first="Jeannie" last="Mui">Jeannie Mui</name><affiliation><mods:affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Vali, Hojatollah" sort="Vali, Hojatollah" uniqKey="Vali H" first="Hojatollah" last="Vali">Hojatollah Vali</name><affiliation><mods:affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Fillebeen, Carine" sort="Fillebeen, Carine" uniqKey="Fillebeen C" first="Carine" last="Fillebeen">Carine Fillebeen</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Pantopoulos, Kostas" sort="Pantopoulos, Kostas" uniqKey="Pantopoulos K" first="Kostas" last="Pantopoulos">Kostas Pantopoulos</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Wu, Ting I" sort="Wu, Ting I" uniqKey="Wu T" first="Ting-Di" last="Wu">Ting-Di Wu</name><affiliation><mods:affiliation>INSERM, U759, Orsay, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</mods:affiliation></affiliation></author><author><name sortKey="Guerquin Ern, Jean Uc" sort="Guerquin Ern, Jean Uc" uniqKey="Guerquin Ern J" first="Jean-Luc" last="Guerquin-Kern">Jean-Luc Guerquin-Kern</name><affiliation><mods:affiliation>INSERM, U759, Orsay, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</mods:affiliation></affiliation></author><author><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.E‐mail:</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: hyman.schipper@mcgill.ca</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F0D5E4339A4E31F36CA2940BEFAE38B0561B7008</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1111/j.1471-4159.2012.07914.x</idno><idno type="url">https://api-v5.istex.fr/document/F0D5E4339A4E31F36CA2940BEFAE38B0561B7008/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001A01</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001A01</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title><author><name sortKey="Song, Wei" sort="Song, Wei" uniqKey="Song W" first="Wei" last="Song">Wei Song</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Zukor, Hillel" sort="Zukor, Hillel" uniqKey="Zukor H" first="Hillel" last="Zukor">Hillel Zukor</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Lin, Shih Siung" sort="Lin, Shih Siung" uniqKey="Lin S" first="Shih-Hsiung" last="Lin">Shih-Hsiung Lin</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Liberman, Adrienne" sort="Liberman, Adrienne" uniqKey="Liberman A" first="Adrienne" last="Liberman">Adrienne Liberman</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Tavitian, Ayda" sort="Tavitian, Ayda" uniqKey="Tavitian A" first="Ayda" last="Tavitian">Ayda Tavitian</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Mui, Jeannie" sort="Mui, Jeannie" uniqKey="Mui J" first="Jeannie" last="Mui">Jeannie Mui</name><affiliation><mods:affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Vali, Hojatollah" sort="Vali, Hojatollah" uniqKey="Vali H" first="Hojatollah" last="Vali">Hojatollah Vali</name><affiliation><mods:affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Fillebeen, Carine" sort="Fillebeen, Carine" uniqKey="Fillebeen C" first="Carine" last="Fillebeen">Carine Fillebeen</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Pantopoulos, Kostas" sort="Pantopoulos, Kostas" uniqKey="Pantopoulos K" first="Kostas" last="Pantopoulos">Kostas Pantopoulos</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Wu, Ting I" sort="Wu, Ting I" uniqKey="Wu T" first="Ting-Di" last="Wu">Ting-Di Wu</name><affiliation><mods:affiliation>INSERM, U759, Orsay, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</mods:affiliation></affiliation></author><author><name sortKey="Guerquin Ern, Jean Uc" sort="Guerquin Ern, Jean Uc" uniqKey="Guerquin Ern J" first="Jean-Luc" last="Guerquin-Kern">Jean-Luc Guerquin-Kern</name><affiliation><mods:affiliation>INSERM, U759, Orsay, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</mods:affiliation></affiliation></author><author><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><affiliation><mods:affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</mods:affiliation></affiliation><affiliation><mods:affiliation>Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.E‐mail:</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: hyman.schipper@mcgill.ca</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Neurochemistry</title><title level="j" type="abbrev">J. Neurochem.</title><idno type="ISSN">0022-3042</idno><idno type="eISSN">1471-4159</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2012-10">2012-10</date><biblScope unit="volume">123</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="325">325</biblScope><biblScope unit="page" to="336">336</biblScope></imprint><idno type="ISSN">0022-3042</idno></series><idno type="istex">F0D5E4339A4E31F36CA2940BEFAE38B0561B7008</idno><idno type="DOI">10.1111/j.1471-4159.2012.07914.x</idno><idno type="ArticleID">JNC7914</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3042</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian CNS remain poorly understood. The stress protein, HO‐1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and CO and is up‐regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. HO‐1 induction in primary astroglial cultures promotes deposition of non‐transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial HO‐1 in vivo, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional GFAP.HMOX1 transgenic mice that selectively over‐express human HO‐1 in the astrocytic compartment. At 48 weeks, the GFAP.HMOX1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron‐regulatory and iron‐binding proteins relative to age‐matched wild‐type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO− signals in the transgenic, but not wild‐type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by TEM. Sustained up‐regulation of HO‐1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease‐affected neural tissues. Curtailment of glial HO‐1 hyperactivity may limit iron‐mediated cytotoxicity in aging and degenerating neural tissues.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Wei Song</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Hillel Zukor</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</json:string><json:string>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Shih‐Hsiung Lin</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</json:string><json:string>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Adrienne Liberman</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Ayda Tavitian</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</json:string><json:string>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Jeannie Mui</name><affiliations><json:string>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</json:string><json:string>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Hojatollah Vali</name><affiliations><json:string>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</json:string><json:string>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Carine Fillebeen</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Kostas Pantopoulos</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</json:string><json:string>Department of Medicine, McGill University, Quebec, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Ting‐Di Wu</name><affiliations><json:string>INSERM, U759, Orsay, France</json:string><json:string>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</json:string></affiliations></json:item><json:item><name>Jean‐Luc Guerquin‐Kern</name><affiliations><json:string>INSERM, U759, Orsay, France</json:string><json:string>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</json:string></affiliations></json:item><json:item><name>Hyman M. Schipper</name><affiliations><json:string>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</json:string><json:string>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</json:string><json:string>Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.E‐mail:</json:string><json:string>E-mail: hyman.schipper@mcgill.ca</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>aging</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>astrocyte</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>heme oxygenase‐1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>iron</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>macroautophagy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>transgenic mice</value></json:item></subject><articleId><json:string>JNC7914</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><qualityIndicators><score>7.52</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 805.039 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1605</abstractCharCount><pdfWordCount>7172</pdfWordCount><pdfCharCount>47353</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>210</abstractWordCount></qualityIndicators><title>Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title><genre><json:string>article</json:string></genre><host><title>Journal of Neurochemistry</title><language><json:string>unknown</json:string></language><doi><json:string>10.1111/(ISSN)1471-4159</json:string></doi><issn><json:string>0022-3042</json:string></issn><eissn><json:string>1471-4159</json:string></eissn><publisherId><json:string>JNC</json:string></publisherId><volume>123</volume><issue>2</issue><pages><first>325</first><last>336</last><total>12</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>ORIGINAL ARTICLE</value></json:item></subject></host><categories><wos><json:string>science</json:string><json:string>neurosciences</json:string><json:string>biochemistry & molecular biology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>neurology & neurosurgery</json:string></scienceMetrix></categories><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1111/j.1471-4159.2012.07914.x</json:string></doi><id>F0D5E4339A4E31F36CA2940BEFAE38B0561B7008</id><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api-v5.istex.fr/document/F0D5E4339A4E31F36CA2940BEFAE38B0561B7008/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api-v5.istex.fr/document/F0D5E4339A4E31F36CA2940BEFAE38B0561B7008/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api-v5.istex.fr/document/F0D5E4339A4E31F36CA2940BEFAE38B0561B7008/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Blackwell Publishing Ltd</publisher><availability><p>© 2012 International Society for Neurochemistry© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry</p></availability><date>2012-08-14</date></publicationStmt><notesStmt><note>Canadian Institutes of Health Research - No. MOP‐68887;</note><note>Mary Katz Claman Foundation</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title><author xml:id="author-1"><persName><forename type="first">Wei</forename><surname>Song</surname></persName><note type="biography">These authors contributed equally to this work.</note><affiliation>These authors contributed equally to this work.</affiliation><affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-2"><persName><forename type="first">Hillel</forename><surname>Zukor</surname></persName><note type="biography">These authors contributed equally to this work.</note><affiliation>These authors contributed equally to this work.</affiliation><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-3"><persName><forename type="first">Shih‐Hsiung</forename><surname>Lin</surname></persName><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-4"><persName><forename type="first">Adrienne</forename><surname>Liberman</surname></persName><affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-5"><persName><forename type="first">Ayda</forename><surname>Tavitian</surname></persName><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-6"><persName><forename type="first">Jeannie</forename><surname>Mui</surname></persName><affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</affiliation><affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-7"><persName><forename type="first">Hojatollah</forename><surname>Vali</surname></persName><affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</affiliation><affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-8"><persName><forename type="first">Carine</forename><surname>Fillebeen</surname></persName><affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-9"><persName><forename type="first">Kostas</forename><surname>Pantopoulos</surname></persName><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Medicine, McGill University, Quebec, Montreal, Canada</affiliation></author><author xml:id="author-10"><persName><forename type="first">Ting‐Di</forename><surname>Wu</surname></persName><affiliation>INSERM, U759, Orsay, France</affiliation><affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</affiliation></author><author xml:id="author-11"><persName><forename type="first">Jean‐Luc</forename><surname>Guerquin‐Kern</surname></persName><affiliation>INSERM, U759, Orsay, France</affiliation><affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</affiliation></author><author xml:id="author-12"><persName><forename type="first">Hyman M.</forename><surname>Schipper</surname></persName><email>hyman.schipper@mcgill.ca</email><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation><affiliation>Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.E‐mail:</affiliation></author></analytic><monogr><title level="j">Journal of Neurochemistry</title><title level="j" type="abbrev">J. Neurochem.</title><idno type="pISSN">0022-3042</idno><idno type="eISSN">1471-4159</idno><idno type="DOI">10.1111/(ISSN)1471-4159</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2012-10"></date><biblScope unit="volume">123</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="325">325</biblScope><biblScope unit="page" to="336">336</biblScope></imprint></monogr><idno type="istex">F0D5E4339A4E31F36CA2940BEFAE38B0561B7008</idno><idno type="DOI">10.1111/j.1471-4159.2012.07914.x</idno><idno type="ArticleID">JNC7914</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012-08-14</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian CNS remain poorly understood. The stress protein, HO‐1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and CO and is up‐regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. HO‐1 induction in primary astroglial cultures promotes deposition of non‐transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial HO‐1 in vivo, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional GFAP.HMOX1 transgenic mice that selectively over‐express human HO‐1 in the astrocytic compartment. At 48 weeks, the GFAP.HMOX1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron‐regulatory and iron‐binding proteins relative to age‐matched wild‐type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO− signals in the transgenic, but not wild‐type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by TEM. Sustained up‐regulation of HO‐1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease‐affected neural tissues. Curtailment of glial HO‐1 hyperactivity may limit iron‐mediated cytotoxicity in aging and degenerating neural tissues.</p></abstract><abstract style="graphical"><p>This study was performed to determine the effects of astroglial HMOX1 expression on brain iron deposition in vivo. The main finding was that over‐expression of human HO‐1 in astrocytes promotes unregulated brain iron deposition and mitophagy in novel GFAP.HMOX1 transgenic mice. Suppression of glial HO‐1 activity may mitigate pathological iron deposition and neuronal damage in Parkinson disease, Alzheimer disease and other aging‐related human neurodegenerative disorders.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>aging</term></item><item><term>astrocyte</term></item><item><term>heme oxygenase‐1</term></item><item><term>iron</term></item><item><term>macroautophagy</term></item><item><term>transgenic mice</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>ORIGINAL ARTICLE</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-06-29">Received</change><change when="2012-08-03">Registration</change><change when="2012-08-14">Created</change><change when="2012-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/F0D5E4339A4E31F36CA2940BEFAE38B0561B7008/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component type="serialArticle" version="2.0" xml:id="jnc7914" xml:lang="en"><header><publicationMeta level="product"><doi origin="wiley" registered="yes">10.1111/(ISSN)1471-4159</doi><issn type="print">0022-3042</issn><issn type="electronic">1471-4159</issn><idGroup><id type="product" value="JNC"></id></idGroup><titleGroup><title sort="JOURNAL OF NEUROCHEMISTRY" type="main">Journal of Neurochemistry</title><title type="short">J. Neurochem.</title></titleGroup></publicationMeta><publicationMeta level="part" position="11102"><doi origin="wiley">10.1111/jnc.2012.123.issue-2</doi><copyright ownership="thirdParty">© 2012 International Society for Neurochemistry</copyright><numberingGroup><numbering type="journalVolume" number="123">123</numbering><numbering type="journalIssue">2</numbering></numberingGroup><coverDate startDate="2012-10">October 2012</coverDate></publicationMeta><publicationMeta level="unit" position="12" status="forIssue" type="article"><doi>10.1111/j.1471-4159.2012.07914.x</doi><idGroup><id type="unit" value="JNC7914"></id></idGroup><countGroup><count number="12" type="pageTotal"></count></countGroup><titleGroup><title type="tocHeading1">ORIGINAL ARTICLES</title><title type="tocHeading2">Molecular Basis of Disease</title><title type="articleCategory">ORIGINAL ARTICLE</title></titleGroup><copyright ownership="thirdParty">© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry</copyright><eventGroup><event date="2012-06-29" type="manuscriptReceived"></event><event date="2012-08-03" type="manuscriptRevised"></event><event date="2012-08-03" type="manuscriptAccepted"></event><event agent="SPS" date="2012-08-14" type="xmlCreated"></event><event type="publishedOnlineAccepted" date="2012-08-07"></event><event type="publishedOnlineEarlyUnpaginated" date="2012-09-03"></event><event type="publishedOnlineFinalForm" date="2012-10-01"></event><event type="firstOnline" date="2012-09-03"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-20"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.3.7 mode:FullText" date="2015-03-24"></event></eventGroup><numberingGroup><numbering type="pageFirst">325</numbering><numbering type="pageLast">336</numbering></numberingGroup><correspondenceTo><lineatedText><line>Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.</line><line>E‐mail: <email>hyman.schipper@mcgill.ca</email></line></lineatedText></correspondenceTo><selfCitationGroup><citation type="self" xml:id="jnc7914-cit-0199"><i>J. Neurochem</i>. (2012) <b>123</b>, 325–336.</citation></selfCitationGroup><linkGroup><link type="toTypesetVersion" href="file:JNC.JNC7914.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Unregulated brain iron deposition in transgenic mice over‐expressing <i><fc>HMOX</fc>1</i> in the astrocytic compartment</title><title type="shortAuthors">W. Song <i>et al</i>.</title></titleGroup><creators><creator affiliationRef="#jnc7914-aff-0001" creatorRole="author" noteRef="#jnc7914-note-0001" xml:id="jnc7914-cr-0001"><personName><givenNames>Wei</givenNames> <familyName>Song</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001 #jnc7914-aff-0002" creatorRole="author" noteRef="#jnc7914-note-0001" xml:id="jnc7914-cr-0002"><personName><givenNames>Hillel</givenNames> <familyName>Zukor</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001 #jnc7914-aff-0002" creatorRole="author" xml:id="jnc7914-cr-0003"><personName><givenNames>Shih‐Hsiung</givenNames> <familyName>Lin</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001" creatorRole="author" xml:id="jnc7914-cr-0004"><personName><givenNames>Adrienne</givenNames> <familyName>Liberman</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001 #jnc7914-aff-0002" creatorRole="author" xml:id="jnc7914-cr-0005"><personName><givenNames>Ayda</givenNames> <familyName>Tavitian</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0003 #jnc7914-aff-0004" creatorRole="author" xml:id="jnc7914-cr-0006"><personName><givenNames>Jeannie</givenNames> <familyName>Mui</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0003 #jnc7914-aff-0004" creatorRole="author" xml:id="jnc7914-cr-0007"><personName><givenNames>Hojatollah</givenNames> <familyName>Vali</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001" creatorRole="author" xml:id="jnc7914-cr-0008"><personName><givenNames>Carine</givenNames> <familyName>Fillebeen</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001 #jnc7914-aff-0005" creatorRole="author" xml:id="jnc7914-cr-0009"><personName><givenNames>Kostas</givenNames> <familyName>Pantopoulos</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0006 #jnc7914-aff-0007" creatorRole="author" xml:id="jnc7914-cr-0010"><personName><givenNames>Ting‐Di</givenNames> <familyName>Wu</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0006 #jnc7914-aff-0007" creatorRole="author" xml:id="jnc7914-cr-0011"><personName><givenNames>Jean‐Luc</givenNames> <familyName>Guerquin‐Kern</familyName></personName></creator><creator affiliationRef="#jnc7914-aff-0001 #jnc7914-aff-0002" corresponding="yes" creatorRole="author" xml:id="jnc7914-cr-0012"><personName><givenNames>Hyman M.</givenNames> <familyName>Schipper</familyName></personName></creator></creators><affiliationGroup><affiliation countryCode="CA" type="organization" xml:id="jnc7914-aff-0001"><orgDiv>Lady Davis Institute</orgDiv> <orgName>Jewish General Hospital</orgName> <address><city>Montreal</city> <countryPart>Quebec</countryPart> <country>Canada</country></address></affiliation><affiliation countryCode="CA" type="organization" xml:id="jnc7914-aff-0002"><orgDiv>Department of Neurology and Neurosurgery</orgDiv> <orgName>McGill University</orgName> <address><city>Montreal</city> <countryPart>Quebec</countryPart> <country>Canada</country></address></affiliation><affiliation countryCode="CA" type="organization" xml:id="jnc7914-aff-0003"><orgDiv>Facility for Electron Microscopy Research</orgDiv> <orgName>McGill University</orgName> <address><city>Montreal</city> <countryPart>Quebec</countryPart> <country>Canada</country></address></affiliation><affiliation countryCode="CA" type="organization" xml:id="jnc7914-aff-0004"><orgDiv>Department of Anatomy and Cell Biology</orgDiv> <orgDiv>Faculty of Medicine</orgDiv> <orgName>McGill University</orgName> <address><city>Montreal</city> <countryPart>Quebec</countryPart> <country>Canada</country></address></affiliation><affiliation countryCode="CA" type="organization" xml:id="jnc7914-aff-0005"><orgDiv>Department of Medicine</orgDiv> <orgName>McGill University</orgName> <address><city>Montreal</city> <countryPart>Quebec</countryPart> <country>Canada</country></address></affiliation><affiliation countryCode="FR" type="organization" xml:id="jnc7914-aff-0006"><orgName>INSERM</orgName> <orgName>U759</orgName> <address><city>Orsay</city> <country>France</country></address></affiliation><affiliation countryCode="FR" type="organization" xml:id="jnc7914-aff-0007"><orgDiv>Laboratoire de Microscopie Ionique</orgDiv> <orgName>Institut Curie</orgName> <address><city>Orsay</city> <country>France</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="jnc7914-kwd-0001">aging</keyword><keyword xml:id="jnc7914-kwd-0002">astrocyte</keyword><keyword xml:id="jnc7914-kwd-0003">heme oxygenase‐1</keyword><keyword xml:id="jnc7914-kwd-0004">iron</keyword><keyword xml:id="jnc7914-kwd-0005">macroautophagy</keyword><keyword xml:id="jnc7914-kwd-0006">transgenic mice</keyword></keywordGroup><fundingInfo><fundingAgency>Canadian Institutes of Health Research</fundingAgency><fundingNumber>MOP‐68887</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Mary Katz Claman Foundation</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:id="jnc7914-abs-0001"><title type="main">Abstract</title><p>The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian <fc>CNS</fc> remain poorly understood. The stress protein, <fc>HO</fc>‐1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and <fc>CO</fc> and is up‐regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. <fc>HO</fc>‐1 induction in primary astroglial cultures promotes deposition of non‐transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial <fc>HO</fc>‐1 <i>in vivo</i>, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional <fc>GFAP</fc>.<fc>HMOX</fc>1 transgenic mice that selectively over‐express human <fc>HO</fc>‐1 in the astrocytic compartment. At 48 weeks, the <fc>GFAP</fc>.<fc>HMOX</fc>1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron‐regulatory and iron‐binding proteins relative to age‐matched wild‐type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO<sup>−</sup> signals in the transgenic, but not wild‐type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by <fc>TEM</fc>. Sustained up‐regulation of <fc>HO</fc>‐1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease‐affected neural tissues. Curtailment of glial <fc>HO</fc>‐1 hyperactivity may limit iron‐mediated cytotoxicity in aging and degenerating neural tissues.</p></abstract><abstract type="graphical" xml:id="jnc7914-abs-0002"><p>This study was performed to determine the effects of astroglial HMOX1 expression on brain iron deposition <i>in vivo</i>. The main finding was that over‐expression of human HO‐1 in astrocytes promotes unregulated brain iron deposition and mitophagy in novel GFAP.HMOX1 transgenic mice. Suppression of glial HO‐1 activity may mitigate pathological iron deposition and neuronal damage in Parkinson disease, Alzheimer disease and other aging‐related human neurodegenerative disorders.<blockFixed type="graphic" xml:id="jnc7914-blkfxd-0001"><mediaResourceGroup><mediaResource alt="image" href="urn:x-wiley:00223042:media:jnc7914:jnc7914-toc-0001"></mediaResource></mediaResourceGroup></blockFixed></p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="jnc7914-note-0001">These authors contributed equally to this work.</note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment</title></titleInfo><name type="personal"><namePart type="given">Wei</namePart><namePart type="family">Song</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hillel</namePart><namePart type="family">Zukor</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation><description>These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shih‐Hsiung</namePart><namePart type="family">Lin</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adrienne</namePart><namePart type="family">Liberman</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ayda</namePart><namePart type="family">Tavitian</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeannie</namePart><namePart type="family">Mui</namePart><affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</affiliation><affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hojatollah</namePart><namePart type="family">Vali</namePart><affiliation>Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada</affiliation><affiliation>Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carine</namePart><namePart type="family">Fillebeen</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kostas</namePart><namePart type="family">Pantopoulos</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Medicine, McGill University, Quebec, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ting‐Di</namePart><namePart type="family">Wu</namePart><affiliation>INSERM, U759, Orsay, France</affiliation><affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean‐Luc</namePart><namePart type="family">Guerquin‐Kern</namePart><affiliation>INSERM, U759, Orsay, France</affiliation><affiliation>Laboratoire de Microscopie Ionique, Institut Curie, Orsay, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hyman M.</namePart><namePart type="family">Schipper</namePart><affiliation>Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada</affiliation><affiliation>Department of Neurology and Neurosurgery, McGill University, Quebec, Montreal, Canada</affiliation><affiliation>Address correspondence and reprint requests to Hyman M. Schipper, Lady Davis Institute, Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, Quebec H3T 1E2, Canada.E‐mail:</affiliation><affiliation>E-mail: hyman.schipper@mcgill.ca</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2012-10</dateIssued><dateCreated encoding="w3cdtf">2012-08-14</dateCreated><dateCaptured encoding="w3cdtf">2012-06-29</dateCaptured><dateValid encoding="w3cdtf">2012-08-03</dateValid><edition>J. Neurochem. (2012) 123, 325–336.</edition><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian CNS remain poorly understood. The stress protein, HO‐1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and CO and is up‐regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. HO‐1 induction in primary astroglial cultures promotes deposition of non‐transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial HO‐1 in vivo, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional GFAP.HMOX1 transgenic mice that selectively over‐express human HO‐1 in the astrocytic compartment. At 48 weeks, the GFAP.HMOX1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron‐regulatory and iron‐binding proteins relative to age‐matched wild‐type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO− signals in the transgenic, but not wild‐type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by TEM. Sustained up‐regulation of HO‐1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease‐affected neural tissues. Curtailment of glial HO‐1 hyperactivity may limit iron‐mediated cytotoxicity in aging and degenerating neural tissues.</abstract><abstract type="graphical">This study was performed to determine the effects of astroglial HMOX1 expression on brain iron deposition in vivo. The main finding was that over‐expression of human HO‐1 in astrocytes promotes unregulated brain iron deposition and mitophagy in novel GFAP.HMOX1 transgenic mice. Suppression of glial HO‐1 activity may mitigate pathological iron deposition and neuronal damage in Parkinson disease, Alzheimer disease and other aging‐related human neurodegenerative disorders.</abstract><note type="funding">Canadian Institutes of Health Research - No. MOP‐68887; </note><note type="funding">Mary Katz Claman Foundation</note><subject><genre>keywords</genre><topic>aging</topic><topic>astrocyte</topic><topic>heme oxygenase‐1</topic><topic>iron</topic><topic>macroautophagy</topic><topic>transgenic mice</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neurochemistry</title></titleInfo><titleInfo type="abbreviated"><title>J. Neurochem.</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>ORIGINAL ARTICLE</topic></subject><identifier type="ISSN">0022-3042</identifier><identifier type="eISSN">1471-4159</identifier><identifier type="DOI">10.1111/(ISSN)1471-4159</identifier><identifier type="PublisherID">JNC</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>123</number></detail><detail type="issue"><caption>no.</caption><number>2</number></detail><extent unit="pages"><start>325</start><end>336</end><total>12</total></extent></part></relatedItem><identifier type="istex">F0D5E4339A4E31F36CA2940BEFAE38B0561B7008</identifier><identifier type="DOI">10.1111/j.1471-4159.2012.07914.x</identifier><identifier type="ArticleID">JNC7914</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2012 International Society for Neurochemistry© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001A01 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 001A01 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Canada
|area= ParkinsonCanadaV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:F0D5E4339A4E31F36CA2940BEFAE38B0561B7008
|texte= Unregulated brain iron deposition in transgenic mice over‐expressing HMOX1 in the astrocytic compartment
}}
| This area was generated with Dilib version V0.6.29. |  |