Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment
Identifieur interne : 000158 ( PascalFrancis/Corpus ); précédent : 000157; suivant : 000159Unregulated 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.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
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.
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Format Inist (serveur)
NO : | PASCAL 12-0412033 INIST |
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ET : | Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment |
AU : | WEI SONG; ZUKOR (Hillel); LIN (Shih-Hsiung); LIBERMAN (Adrienne); TAVITIAN (Ayda); MUI (Jeannie); VALI (Hojatollah); FILLEBEEN (Carine); PANTOPOULOS (Kostas); WU (Ting-Di); GUERQUIN-KERN (Jean-Luc); SCHIPPER (Hyman M.) |
AF : | Lady Davis Institute, Jewish General Hospital/Montreal, Quebec/Canada (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 8 aut., 9 aut., 12 aut.); Department of Neurology and Neurosurgery, McGill University/Montreal, Quebec/Canada (2 aut., 3 aut., 5 aut., 12 aut.); Facility for Electron Microscopy Research, McGill University/Montreal, Quebec/Canada (6 aut., 7 aut.); Department of Anatomy and Cell Biolagy, Faculty of Medicine, McGill University/Montreal, Quebec/Canada (6 aut., 7 aut.); Department of Medicine, McGill University/Montreal, Quebec/Canada (9 aut.); INSERM/U759, Orsay/France (10 aut., 11 aut.); Laboratoire de Microscopie Ionique, Institut Curie/Orsay/France (10 aut., 11 aut.) |
DT : | Publication en série; Niveau analytique |
SO : | Journal of neurochemistry; ISSN 0022-3042; Coden JONRA9; Royaume-Uni; Da. 2012; Vol. 123; No. 1-2; Pp. 325-336; Bibl. 2 p. |
LA : | Anglais |
EA : | 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. |
CC : | 002B17G; 002B18C13 |
FD : | Encéphale; Fer; Système nerveux central; Stress; Protéine liaison; Hème; Induction; Culture primaire; Démence d'Alzheimer; Transferrine; Mitochondrie; Maladie de Parkinson; Méthode dynamique; Ion; Souris; Homme |
FG : | Pathologie de l'encéphale; Maladie dégénérative; Pathologie du système nerveux central; Pathologie du système nerveux; Syndrome extrapyramidal; Névroglie; Rodentia; Mammalia; Vertebrata |
ED : | Encephalon; Iron; Central nervous system; Stress; Binding protein; Heme; Induction; Primary culture; Alzheimer disease; Transferrin; Mitochondria; Parkinson disease; Dynamic method; Ions; Mouse; Human |
EG : | Cerebral disorder; Degenerative disease; Central nervous system disease; Nervous system diseases; Extrapyramidal syndrome; Neuroglia; Rodentia; Mammalia; Vertebrata |
SD : | Encéfalo; Hierro; Sistema nervioso central; Estrés; Proteína enlace; Heme; Inducción; Cultivo primario; Demencia Alzheimer; Transferrina; Mitocondria; Parkinson enfermedad; Método dinámico; Ión; Ratón; Hombre |
LO : | INIST-4037.354000506820050290 |
ID : | 12-0412033 |
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Pascal:12-0412033Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment</title>
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<author><name sortKey="Guerquin Kern, Jean Luc" sort="Guerquin Kern, Jean Luc" uniqKey="Guerquin Kern J" first="Jean-Luc" last="Guerquin-Kern">Jean-Luc Guerquin-Kern</name>
<affiliation><inist:fA14 i1="06"><s1>INSERM</s1>
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<sZ>11 aut.</sZ>
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<affiliation><inist:fA14 i1="07"><s1>Laboratoire de Microscopie Ionique, Institut Curie</s1>
<s2>Orsay</s2>
<s3>FRA</s3>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
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<author><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name>
<affiliation><inist:fA14 i1="01"><s1>Lady Davis Institute, Jewish General Hospital</s1>
<s2>Montreal, Quebec</s2>
<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
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<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
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<affiliation><inist:fA14 i1="02"><s1>Department of Neurology and Neurosurgery, McGill University</s1>
<s2>Montreal, Quebec</s2>
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<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
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<series><title level="j" type="main">Journal of neurochemistry</title>
<title level="j" type="abbreviated">J. neurochem.</title>
<idno type="ISSN">0022-3042</idno>
<imprint><date when="2012">2012</date>
</imprint>
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<seriesStmt><title level="j" type="main">Journal of neurochemistry</title>
<title level="j" type="abbreviated">J. neurochem.</title>
<idno type="ISSN">0022-3042</idno>
</seriesStmt>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alzheimer disease</term>
<term>Binding protein</term>
<term>Central nervous system</term>
<term>Dynamic method</term>
<term>Encephalon</term>
<term>Heme</term>
<term>Human</term>
<term>Induction</term>
<term>Ions</term>
<term>Iron</term>
<term>Mitochondria</term>
<term>Mouse</term>
<term>Parkinson disease</term>
<term>Primary culture</term>
<term>Stress</term>
<term>Transferrin</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Encéphale</term>
<term>Fer</term>
<term>Système nerveux central</term>
<term>Stress</term>
<term>Protéine liaison</term>
<term>Hème</term>
<term>Induction</term>
<term>Culture primaire</term>
<term>Démence d'Alzheimer</term>
<term>Transferrine</term>
<term>Mitochondrie</term>
<term>Maladie de Parkinson</term>
<term>Méthode dynamique</term>
<term>Ion</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">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<sup>-</sup>
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>
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<fA05><s2>123</s2>
</fA05>
<fA06><s2>1-2</s2>
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<fA08 i1="01" i2="1" l="ENG"><s1>Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment</s1>
</fA08>
<fA11 i1="01" i2="1"><s1>WEI SONG</s1>
</fA11>
<fA11 i1="02" i2="1"><s1>ZUKOR (Hillel)</s1>
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<fA11 i1="03" i2="1"><s1>LIN (Shih-Hsiung)</s1>
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<fA11 i1="04" i2="1"><s1>LIBERMAN (Adrienne)</s1>
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<fA11 i1="05" i2="1"><s1>TAVITIAN (Ayda)</s1>
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<fA11 i1="06" i2="1"><s1>MUI (Jeannie)</s1>
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<fA11 i1="07" i2="1"><s1>VALI (Hojatollah)</s1>
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<fA11 i1="08" i2="1"><s1>FILLEBEEN (Carine)</s1>
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<fA11 i1="09" i2="1"><s1>PANTOPOULOS (Kostas)</s1>
</fA11>
<fA11 i1="10" i2="1"><s1>WU (Ting-Di)</s1>
</fA11>
<fA11 i1="11" i2="1"><s1>GUERQUIN-KERN (Jean-Luc)</s1>
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<fA11 i1="12" i2="1"><s1>SCHIPPER (Hyman M.)</s1>
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<fA14 i1="01"><s1>Lady Davis Institute, Jewish General Hospital</s1>
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<s3>CAN</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</fA14>
<fA14 i1="02"><s1>Department of Neurology and Neurosurgery, McGill University</s1>
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<s3>CAN</s3>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>12 aut.</sZ>
</fA14>
<fA14 i1="03"><s1>Facility for Electron Microscopy Research, McGill University</s1>
<s2>Montreal, Quebec</s2>
<s3>CAN</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
</fA14>
<fA14 i1="04"><s1>Department of Anatomy and Cell Biolagy, Faculty of Medicine, McGill University</s1>
<s2>Montreal, Quebec</s2>
<s3>CAN</s3>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
</fA14>
<fA14 i1="05"><s1>Department of Medicine, McGill University</s1>
<s2>Montreal, Quebec</s2>
<s3>CAN</s3>
<sZ>9 aut.</sZ>
</fA14>
<fA14 i1="06"><s1>INSERM</s1>
<s2>U759, Orsay</s2>
<s3>FRA</s3>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</fA14>
<fA14 i1="07"><s1>Laboratoire de Microscopie Ionique, Institut Curie</s1>
<s2>Orsay</s2>
<s3>FRA</s3>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
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<fA20><s1>325-336</s1>
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<fA21><s1>2012</s1>
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<fA43 i1="01"><s1>INIST</s1>
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<s5>354000506820050290</s5>
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<fA44><s0>0000</s0>
<s1>© 2012 INIST-CNRS. All rights reserved.</s1>
</fA44>
<fA45><s0>2 p.</s0>
</fA45>
<fA47 i1="01" i2="1"><s0>12-0412033</s0>
</fA47>
<fA60><s1>P</s1>
</fA60>
<fA61><s0>A</s0>
</fA61>
<fA64 i1="01" i2="1"><s0>Journal of neurochemistry</s0>
</fA64>
<fA66 i1="01"><s0>GBR</s0>
</fA66>
<fC01 i1="01" l="ENG"><s0>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<sup>-</sup>
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.</s0>
</fC01>
<fC02 i1="01" i2="X"><s0>002B17G</s0>
</fC02>
<fC02 i1="02" i2="X"><s0>002B18C13</s0>
</fC02>
<fC03 i1="01" i2="X" l="FRE"><s0>Encéphale</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="ENG"><s0>Encephalon</s0>
<s5>01</s5>
</fC03>
<fC03 i1="01" i2="X" l="SPA"><s0>Encéfalo</s0>
<s5>01</s5>
</fC03>
<fC03 i1="02" i2="X" l="FRE"><s0>Fer</s0>
<s2>NC</s2>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Iron</s0>
<s2>NC</s2>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="SPA"><s0>Hierro</s0>
<s2>NC</s2>
<s5>02</s5>
</fC03>
<fC03 i1="03" i2="X" l="FRE"><s0>Système nerveux central</s0>
<s5>03</s5>
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<fC03 i1="03" i2="X" l="ENG"><s0>Central nervous system</s0>
<s5>03</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA"><s0>Sistema nervioso central</s0>
<s5>03</s5>
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<fC03 i1="04" i2="X" l="FRE"><s0>Stress</s0>
<s5>04</s5>
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<fC03 i1="04" i2="X" l="ENG"><s0>Stress</s0>
<s5>04</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Estrés</s0>
<s5>04</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Protéine liaison</s0>
<s5>05</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Binding protein</s0>
<s5>05</s5>
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<fC03 i1="05" i2="X" l="SPA"><s0>Proteína enlace</s0>
<s5>05</s5>
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<fC03 i1="06" i2="X" l="FRE"><s0>Hème</s0>
<s5>06</s5>
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<fC03 i1="06" i2="X" l="ENG"><s0>Heme</s0>
<s5>06</s5>
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<fC03 i1="06" i2="X" l="SPA"><s0>Heme</s0>
<s5>06</s5>
</fC03>
<fC03 i1="07" i2="X" l="FRE"><s0>Induction</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="ENG"><s0>Induction</s0>
<s5>07</s5>
</fC03>
<fC03 i1="07" i2="X" l="SPA"><s0>Inducción</s0>
<s5>07</s5>
</fC03>
<fC03 i1="08" i2="X" l="FRE"><s0>Culture primaire</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="ENG"><s0>Primary culture</s0>
<s5>08</s5>
</fC03>
<fC03 i1="08" i2="X" l="SPA"><s0>Cultivo primario</s0>
<s5>08</s5>
</fC03>
<fC03 i1="09" i2="X" l="FRE"><s0>Démence d'Alzheimer</s0>
<s5>09</s5>
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<fC03 i1="09" i2="X" l="ENG"><s0>Alzheimer disease</s0>
<s5>09</s5>
</fC03>
<fC03 i1="09" i2="X" l="SPA"><s0>Demencia Alzheimer</s0>
<s5>09</s5>
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<fC03 i1="10" i2="X" l="FRE"><s0>Transferrine</s0>
<s5>10</s5>
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<s5>10</s5>
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<s5>11</s5>
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<fC03 i1="12" i2="X" l="FRE"><s0>Maladie de Parkinson</s0>
<s2>NM</s2>
<s5>12</s5>
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<fC03 i1="12" i2="X" l="ENG"><s0>Parkinson disease</s0>
<s2>NM</s2>
<s5>12</s5>
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<fC03 i1="12" i2="X" l="SPA"><s0>Parkinson enfermedad</s0>
<s2>NM</s2>
<s5>12</s5>
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<fC03 i1="13" i2="X" l="FRE"><s0>Méthode dynamique</s0>
<s5>13</s5>
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<s5>13</s5>
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<s5>13</s5>
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<s5>14</s5>
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<s5>14</s5>
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<s5>14</s5>
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<s5>54</s5>
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<s5>54</s5>
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<s5>20</s5>
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<s5>20</s5>
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<s5>21</s5>
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<s5>21</s5>
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<s5>22</s5>
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<s5>22</s5>
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<fC07 i1="03" i2="X" l="SPA"><s0>Sistema nervosio central patología</s0>
<s5>22</s5>
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<fC07 i1="04" i2="X" l="FRE"><s0>Pathologie du système nerveux</s0>
<s5>23</s5>
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<s5>23</s5>
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<s5>24</s5>
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<fC07 i1="05" i2="X" l="ENG"><s0>Extrapyramidal syndrome</s0>
<s5>24</s5>
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<fC07 i1="05" i2="X" l="SPA"><s0>Extrapiramidal síndrome</s0>
<s5>24</s5>
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<s5>25</s5>
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<s5>25</s5>
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<s5>25</s5>
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<fC07 i1="07" i2="X" l="FRE"><s0>Rodentia</s0>
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<s2>NS</s2>
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<s2>NS</s2>
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<s2>NS</s2>
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<fC07 i1="08" i2="X" l="SPA"><s0>Mammalia</s0>
<s2>NS</s2>
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<fC07 i1="09" i2="X" l="FRE"><s0>Vertebrata</s0>
<s2>NS</s2>
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<s2>NS</s2>
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<fC07 i1="09" i2="X" l="SPA"><s0>Vertebrata</s0>
<s2>NS</s2>
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<fN21><s1>317</s1>
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<fN44 i1="01"><s1>OTO</s1>
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<fN82><s1>OTO</s1>
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</pA>
</standard>
<server><NO>PASCAL 12-0412033 INIST</NO>
<ET>Unregulated brain iron deposition in transgenic mice over-expressing HMOX1 in the astrocytic compartment</ET>
<AU>WEI SONG; ZUKOR (Hillel); LIN (Shih-Hsiung); LIBERMAN (Adrienne); TAVITIAN (Ayda); MUI (Jeannie); VALI (Hojatollah); FILLEBEEN (Carine); PANTOPOULOS (Kostas); WU (Ting-Di); GUERQUIN-KERN (Jean-Luc); SCHIPPER (Hyman M.)</AU>
<AF>Lady Davis Institute, Jewish General Hospital/Montreal, Quebec/Canada (1 aut., 2 aut., 3 aut., 4 aut., 5 aut., 8 aut., 9 aut., 12 aut.); Department of Neurology and Neurosurgery, McGill University/Montreal, Quebec/Canada (2 aut., 3 aut., 5 aut., 12 aut.); Facility for Electron Microscopy Research, McGill University/Montreal, Quebec/Canada (6 aut., 7 aut.); Department of Anatomy and Cell Biolagy, Faculty of Medicine, McGill University/Montreal, Quebec/Canada (6 aut., 7 aut.); Department of Medicine, McGill University/Montreal, Quebec/Canada (9 aut.); INSERM/U759, Orsay/France (10 aut., 11 aut.); Laboratoire de Microscopie Ionique, Institut Curie/Orsay/France (10 aut., 11 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Journal of neurochemistry; ISSN 0022-3042; Coden JONRA9; Royaume-Uni; Da. 2012; Vol. 123; No. 1-2; Pp. 325-336; Bibl. 2 p.</SO>
<LA>Anglais</LA>
<EA>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<sup>-</sup>
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.</EA>
<CC>002B17G; 002B18C13</CC>
<FD>Encéphale; Fer; Système nerveux central; Stress; Protéine liaison; Hème; Induction; Culture primaire; Démence d'Alzheimer; Transferrine; Mitochondrie; Maladie de Parkinson; Méthode dynamique; Ion; Souris; Homme</FD>
<FG>Pathologie de l'encéphale; Maladie dégénérative; Pathologie du système nerveux central; Pathologie du système nerveux; Syndrome extrapyramidal; Névroglie; Rodentia; Mammalia; Vertebrata</FG>
<ED>Encephalon; Iron; Central nervous system; Stress; Binding protein; Heme; Induction; Primary culture; Alzheimer disease; Transferrin; Mitochondria; Parkinson disease; Dynamic method; Ions; Mouse; Human</ED>
<EG>Cerebral disorder; Degenerative disease; Central nervous system disease; Nervous system diseases; Extrapyramidal syndrome; Neuroglia; Rodentia; Mammalia; Vertebrata</EG>
<SD>Encéfalo; Hierro; Sistema nervioso central; Estrés; Proteína enlace; Heme; Inducción; Cultivo primario; Demencia Alzheimer; Transferrina; Mitocondria; Parkinson enfermedad; Método dinámico; Ión; Ratón; Hombre</SD>
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<ID>12-0412033</ID>
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