The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis.
Identifieur interne : 000659 ( PubMed/Corpus ); précédent : 000658; suivant : 000660The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis.
Auteurs : Erwann Rousseau ; Patrick P. Michel ; Etienne C. HirschSource :
- Molecular pharmacology [ 1521-0111 ] ; 2013.
English descriptors
- KwdEn :
- 1-Methyl-4-phenylpyridinium (toxicity), Animals, Binding Sites, Calcium (metabolism), Cell Death (drug effects), Cells, Cultured, Dopamine (metabolism), Focal Adhesion Kinase 1 (antagonists & inhibitors), Focal Adhesion Kinase 1 (metabolism), Glial Cell Line-Derived Neurotrophic Factor (metabolism), Homeostasis, Humans, Lactoferrin (metabolism), Lactoferrin (pharmacology), Mesencephalon (cytology), Mitochondria (drug effects), Mitochondria (metabolism), Nerve Degeneration (metabolism), Nerve Degeneration (pathology), Neuroglia (drug effects), Neuroglia (pathology), Neurons (metabolism), Neurons (pathology), Parkinson Disease (metabolism), Parkinson Disease (pathology), Phosphatidylinositol 3-Kinases (metabolism), Rats, Rats, Wistar, Recombinant Proteins (metabolism), Recombinant Proteins (pharmacology).
- MESH :
- chemical , antagonists & inhibitors : Focal Adhesion Kinase 1.
- chemical , metabolism : Calcium, Dopamine, Focal Adhesion Kinase 1, Glial Cell Line-Derived Neurotrophic Factor, Lactoferrin, Phosphatidylinositol 3-Kinases, Recombinant Proteins.
- chemical , pharmacology : Lactoferrin, Recombinant Proteins.
- chemical , toxicity : 1-Methyl-4-phenylpyridinium.
- cytology : Mesencephalon.
- drug effects : Cell Death, Mitochondria, Neuroglia.
- metabolism : Mitochondria, Nerve Degeneration, Neurons, Parkinson Disease.
- pathology : Nerve Degeneration, Neuroglia, Neurons, Parkinson Disease.
- Animals, Binding Sites, Cells, Cultured, Homeostasis, Humans, Rats, Rats, Wistar.
Abstract
Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, further supporting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.
DOI: 10.1124/mol.113.087965
PubMed: 24077968
Links to Exploration step
pubmed:24077968Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis.</title><author><name sortKey="Rousseau, Erwann" sort="Rousseau, Erwann" uniqKey="Rousseau E" first="Erwann" last="Rousseau">Erwann Rousseau</name><affiliation><nlm:affiliation>Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) S975, Institut du Cerveau et de la Moelle Epinière, Paris, France; Institut National de la Santé et de la Recherche Médicale, U975, Paris, France; and Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Michel, Patrick P" sort="Michel, Patrick P" uniqKey="Michel P" first="Patrick P" last="Michel">Patrick P. Michel</name></author><author><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C" last="Hirsch">Etienne C. Hirsch</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2013">2013</date><idno type="RBID">pubmed:24077968</idno><idno type="pmid">24077968</idno><idno type="doi">10.1124/mol.113.087965</idno><idno type="wicri:Area/PubMed/Corpus">000659</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000659</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis.</title><author><name sortKey="Rousseau, Erwann" sort="Rousseau, Erwann" uniqKey="Rousseau E" first="Erwann" last="Rousseau">Erwann Rousseau</name><affiliation><nlm:affiliation>Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) S975, Institut du Cerveau et de la Moelle Epinière, Paris, France; Institut National de la Santé et de la Recherche Médicale, U975, Paris, France; and Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Michel, Patrick P" sort="Michel, Patrick P" uniqKey="Michel P" first="Patrick P" last="Michel">Patrick P. Michel</name></author><author><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C" last="Hirsch">Etienne C. Hirsch</name></author></analytic><series><title level="j">Molecular pharmacology</title><idno type="eISSN">1521-0111</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenylpyridinium (toxicity)</term><term>Animals</term><term>Binding Sites</term><term>Calcium (metabolism)</term><term>Cell Death (drug effects)</term><term>Cells, Cultured</term><term>Dopamine (metabolism)</term><term>Focal Adhesion Kinase 1 (antagonists & inhibitors)</term><term>Focal Adhesion Kinase 1 (metabolism)</term><term>Glial Cell Line-Derived Neurotrophic Factor (metabolism)</term><term>Homeostasis</term><term>Humans</term><term>Lactoferrin (metabolism)</term><term>Lactoferrin (pharmacology)</term><term>Mesencephalon (cytology)</term><term>Mitochondria (drug effects)</term><term>Mitochondria (metabolism)</term><term>Nerve Degeneration (metabolism)</term><term>Nerve Degeneration (pathology)</term><term>Neuroglia (drug effects)</term><term>Neuroglia (pathology)</term><term>Neurons (metabolism)</term><term>Neurons (pathology)</term><term>Parkinson Disease (metabolism)</term><term>Parkinson Disease (pathology)</term><term>Phosphatidylinositol 3-Kinases (metabolism)</term><term>Rats</term><term>Rats, Wistar</term><term>Recombinant Proteins (metabolism)</term><term>Recombinant Proteins (pharmacology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Focal Adhesion Kinase 1</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Calcium</term><term>Dopamine</term><term>Focal Adhesion Kinase 1</term><term>Glial Cell Line-Derived Neurotrophic Factor</term><term>Lactoferrin</term><term>Phosphatidylinositol 3-Kinases</term><term>Recombinant Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Lactoferrin</term><term>Recombinant Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>1-Methyl-4-phenylpyridinium</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Mesencephalon</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Death</term><term>Mitochondria</term><term>Neuroglia</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term><term>Nerve Degeneration</term><term>Neurons</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Nerve Degeneration</term><term>Neuroglia</term><term>Neurons</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Binding Sites</term><term>Cells, Cultured</term><term>Homeostasis</term><term>Humans</term><term>Rats</term><term>Rats, Wistar</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, further supporting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24077968</PMID><DateCreated><Year>2013</Year><Month>11</Month><Day>05</Day></DateCreated><DateCompleted><Year>2014</Year><Month>01</Month><Day>06</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>05</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1521-0111</ISSN><JournalIssue CitedMedium="Internet"><Volume>84</Volume><Issue>6</Issue><PubDate><Year>2013</Year><Month>Dec</Month></PubDate></JournalIssue><Title>Molecular pharmacology</Title><ISOAbbreviation>Mol. Pharmacol.</ISOAbbreviation></Journal><ArticleTitle>The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis.</ArticleTitle><Pagination><MedlinePgn>888-98</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1124/mol.113.087965</ELocationID><Abstract><AbstractText>Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, further supporting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rousseau</LastName><ForeName>Erwann</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) S975, Institut du Cerveau et de la Moelle Epinière, Paris, France; Institut National de la Santé et de la Recherche Médicale, U975, Paris, France; and Centre National de la Recherche Scientifique, UMR 7225, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Michel</LastName><ForeName>Patrick P</ForeName><Initials>PP</Initials></Author><Author ValidYN="Y"><LastName>Hirsch</LastName><ForeName>Etienne C</ForeName><Initials>EC</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2013</Year><Month>09</Month><Day>27</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mol Pharmacol</MedlineTA><NlmUniqueID>0035623</NlmUniqueID><ISSNLinking>0026-895X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051100">Glial Cell Line-Derived Neurotrophic Factor</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011994">Recombinant Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.-</RegistryNumber><NameOfSubstance UI="D019869">Phosphatidylinositol 3-Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.2</RegistryNumber><NameOfSubstance UI="D051417">Focal Adhesion Kinase 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.21.-</RegistryNumber><NameOfSubstance UI="D007781">Lactoferrin</NameOfSubstance></Chemical><Chemical><RegistryNumber>R865A5OY8J</RegistryNumber><NameOfSubstance UI="D015655">1-Methyl-4-phenylpyridinium</NameOfSubstance></Chemical><Chemical><RegistryNumber>SY7Q814VUP</RegistryNumber><NameOfSubstance UI="D002118">Calcium</NameOfSubstance></Chemical><Chemical><RegistryNumber>VTD58H1Z2X</RegistryNumber><NameOfSubstance UI="D004298">Dopamine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D015655" MajorTopicYN="N">1-Methyl-4-phenylpyridinium</DescriptorName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding 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