The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells.
Identifieur interne : 000E65 ( PubMed/Corpus ); précédent : 000E64; suivant : 000E66The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells.
Auteurs : Wei Song ; Amar Patel ; Hamid Y. Qureshi ; Dong Han ; Hyman M. Schipper ; Hemant K. PaudelSource :
- Journal of neurochemistry [ 1471-4159 ] ; 2009.
English descriptors
- KwdEn :
- Animals, Gene Expression Regulation, Enzymologic (genetics), Gene Silencing, Heme Oxygenase-1 (biosynthesis), Heme Oxygenase-1 (deficiency), Heme Oxygenase-1 (genetics), Humans, Mutation, Neuroblastoma (enzymology), Neuroblastoma (genetics), Neuroblastoma (metabolism), Parkinson Disease (genetics), Parkinson Disease (metabolism), Proteasome Endopeptidase Complex (genetics), Proteasome Endopeptidase Complex (metabolism), Proteasome Endopeptidase Complex (physiology), Protein Denaturation (genetics), Protein Stability, Rats, Tumor Cells, Cultured, alpha-Synuclein (antagonists & inhibitors), alpha-Synuclein (genetics), alpha-Synuclein (metabolism).
- MESH :
- chemical , antagonists & inhibitors : alpha-Synuclein.
- chemical , biosynthesis : Heme Oxygenase-1.
- chemical , deficiency : Heme Oxygenase-1.
- enzymology : Neuroblastoma.
- genetics : Gene Expression Regulation, Enzymologic, Heme Oxygenase-1, Neuroblastoma, Parkinson Disease, Proteasome Endopeptidase Complex, Protein Denaturation, alpha-Synuclein.
- metabolism : Neuroblastoma, Parkinson Disease, Proteasome Endopeptidase Complex, alpha-Synuclein.
- chemical , physiology : Proteasome Endopeptidase Complex.
- Animals, Gene Silencing, Humans, Mutation, Protein Stability, Rats, Tumor Cells, Cultured.
Abstract
Proteosomal degradation of proteins is one of the major mechanisms of intracellular protein turnover. Failure of the proteosome to degrade misfolded protein is implicated in the accumulation of alpha-synuclein in Parkinson's disease (PD). Heme oxygenase-1 (HO-1), an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor) is expressed in response to various stressors. HO-1 is up-regulated in PD- and Alzheimer's disease-affected neural tissues. In this study, we found that HO-1 over-expression engenders dose-dependent decreases in alpha-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of alpha-synuclein was restored. Likewise, treatment of HO-1 over-expressing cells with the HO-1 inhibitor, tin mesoporphyrin, the iron chelator deferoxamine or antagonist of CO-dependent cGMP activation, methylene blue, mitigated the HO-1-induced reduction in alpha-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of alpha-synuclein was almost completely restored. In contrast to the effect on alpha-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated alpha-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of alpha-synuclein (WT) but not that of A30P. Our results suggest that HO-1, which is expressed when neurons are exposed to toxic stimuli capable of inducing protein misfolding, triggers proteosomal degradation of proteins and prevents intracellular accumulation of protein aggregates and inclusions. Resistance to HO-1 induced proteosomal degradation may render the familial PD-associated A30P mutation prone to toxic intracellular aggregation.
DOI: 10.1111/j.1471-4159.2009.06165.x
PubMed: 19457084
Links to Exploration step
pubmed:19457084Le document en format XML
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Qureshi</name></author><author><name sortKey="Han, Dong" sort="Han, Dong" uniqKey="Han D" first="Dong" last="Han">Dong Han</name></author><author><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M" last="Schipper">Hyman M. Schipper</name></author><author><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K" last="Paudel">Hemant K. Paudel</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2009">2009</date><idno type="RBID">pubmed:19457084</idno><idno type="pmid">19457084</idno><idno type="doi">10.1111/j.1471-4159.2009.06165.x</idno><idno type="wicri:Area/PubMed/Corpus">000E65</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000E65</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells.</title><author><name sortKey="Song, Wei" sort="Song, Wei" uniqKey="Song W" first="Wei" last="Song">Wei Song</name><affiliation><nlm:affiliation>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Patel, Amar" sort="Patel, Amar" uniqKey="Patel A" first="Amar" last="Patel">Amar Patel</name></author><author><name sortKey="Qureshi, Hamid Y" sort="Qureshi, Hamid Y" uniqKey="Qureshi H" first="Hamid Y" last="Qureshi">Hamid Y. Qureshi</name></author><author><name sortKey="Han, Dong" sort="Han, Dong" uniqKey="Han D" first="Dong" last="Han">Dong Han</name></author><author><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M" last="Schipper">Hyman M. Schipper</name></author><author><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K" last="Paudel">Hemant K. Paudel</name></author></analytic><series><title level="j">Journal of neurochemistry</title><idno type="eISSN">1471-4159</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Gene Expression Regulation, Enzymologic (genetics)</term><term>Gene Silencing</term><term>Heme Oxygenase-1 (biosynthesis)</term><term>Heme Oxygenase-1 (deficiency)</term><term>Heme Oxygenase-1 (genetics)</term><term>Humans</term><term>Mutation</term><term>Neuroblastoma (enzymology)</term><term>Neuroblastoma (genetics)</term><term>Neuroblastoma (metabolism)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (metabolism)</term><term>Proteasome Endopeptidase Complex (genetics)</term><term>Proteasome Endopeptidase Complex (metabolism)</term><term>Proteasome Endopeptidase Complex (physiology)</term><term>Protein Denaturation (genetics)</term><term>Protein Stability</term><term>Rats</term><term>Tumor Cells, Cultured</term><term>alpha-Synuclein (antagonists & inhibitors)</term><term>alpha-Synuclein (genetics)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Heme Oxygenase-1</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Heme Oxygenase-1</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Gene Expression Regulation, Enzymologic</term><term>Heme Oxygenase-1</term><term>Neuroblastoma</term><term>Parkinson Disease</term><term>Proteasome Endopeptidase Complex</term><term>Protein Denaturation</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neuroblastoma</term><term>Parkinson Disease</term><term>Proteasome Endopeptidase Complex</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Proteasome Endopeptidase Complex</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Gene Silencing</term><term>Humans</term><term>Mutation</term><term>Protein Stability</term><term>Rats</term><term>Tumor Cells, Cultured</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Proteosomal degradation of proteins is one of the major mechanisms of intracellular protein turnover. Failure of the proteosome to degrade misfolded protein is implicated in the accumulation of alpha-synuclein in Parkinson's disease (PD). Heme oxygenase-1 (HO-1), an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor) is expressed in response to various stressors. HO-1 is up-regulated in PD- and Alzheimer's disease-affected neural tissues. In this study, we found that HO-1 over-expression engenders dose-dependent decreases in alpha-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of alpha-synuclein was restored. Likewise, treatment of HO-1 over-expressing cells with the HO-1 inhibitor, tin mesoporphyrin, the iron chelator deferoxamine or antagonist of CO-dependent cGMP activation, methylene blue, mitigated the HO-1-induced reduction in alpha-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of alpha-synuclein was almost completely restored. In contrast to the effect on alpha-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated alpha-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of alpha-synuclein (WT) but not that of A30P. Our results suggest that HO-1, which is expressed when neurons are exposed to toxic stimuli capable of inducing protein misfolding, triggers proteosomal degradation of proteins and prevents intracellular accumulation of protein aggregates and inclusions. Resistance to HO-1 induced proteosomal degradation may render the familial PD-associated A30P mutation prone to toxic intracellular aggregation.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">19457084</PMID><DateCreated><Year>2009</Year><Month>07</Month><Day>08</Day></DateCreated><DateCompleted><Year>2009</Year><Month>07</Month><Day>31</Day></DateCompleted><DateRevised><Year>2016</Year><Month>11</Month><Day>25</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1471-4159</ISSN><JournalIssue CitedMedium="Internet"><Volume>110</Volume><Issue>2</Issue><PubDate><Year>2009</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Journal of neurochemistry</Title><ISOAbbreviation>J. Neurochem.</ISOAbbreviation></Journal><ArticleTitle>The Parkinson disease-associated A30P mutation stabilizes alpha-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells.</ArticleTitle><Pagination><MedlinePgn>719-33</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1111/j.1471-4159.2009.06165.x</ELocationID><Abstract><AbstractText>Proteosomal degradation of proteins is one of the major mechanisms of intracellular protein turnover. Failure of the proteosome to degrade misfolded protein is implicated in the accumulation of alpha-synuclein in Parkinson's disease (PD). Heme oxygenase-1 (HO-1), an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor) is expressed in response to various stressors. HO-1 is up-regulated in PD- and Alzheimer's disease-affected neural tissues. In this study, we found that HO-1 over-expression engenders dose-dependent decreases in alpha-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of alpha-synuclein was restored. Likewise, treatment of HO-1 over-expressing cells with the HO-1 inhibitor, tin mesoporphyrin, the iron chelator deferoxamine or antagonist of CO-dependent cGMP activation, methylene blue, mitigated the HO-1-induced reduction in alpha-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of alpha-synuclein was almost completely restored. In contrast to the effect on alpha-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated alpha-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of alpha-synuclein (WT) but not that of A30P. Our results suggest that HO-1, which is expressed when neurons are exposed to toxic stimuli capable of inducing protein misfolding, triggers proteosomal degradation of proteins and prevents intracellular accumulation of protein aggregates and inclusions. Resistance to HO-1 induced proteosomal degradation may render the familial PD-associated A30P mutation prone to toxic intracellular aggregation.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Song</LastName><ForeName>Wei</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Patel</LastName><ForeName>Amar</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Qureshi</LastName><ForeName>Hamid Y</ForeName><Initials>HY</Initials></Author><Author ValidYN="Y"><LastName>Han</LastName><ForeName>Dong</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Schipper</LastName><ForeName>Hyman M</ForeName><Initials>HM</Initials></Author><Author ValidYN="Y"><LastName>Paudel</LastName><ForeName>Hemant K</ForeName><Initials>HK</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2009</Year><Month>05</Month><Day>13</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Neurochem</MedlineTA><NlmUniqueID>2985190R</NlmUniqueID><ISSNLinking>0022-3042</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051844">alpha-Synuclein</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.14.14.18</RegistryNumber><NameOfSubstance UI="D051547">Heme Oxygenase-1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.25.1</RegistryNumber><NameOfSubstance UI="D046988">Proteasome Endopeptidase Complex</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015971" MajorTopicYN="N">Gene Expression Regulation, Enzymologic</DescriptorName><QualifierName UI="Q000235" 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MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010300" MajorTopicYN="N">Parkinson Disease</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D046988" MajorTopicYN="N">Proteasome Endopeptidase Complex</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011489" MajorTopicYN="N">Protein Denaturation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055550" MajorTopicYN="N">Protein Stability</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051381" 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PubStatus="medline"><Year>2009</Year><Month>8</Month><Day>1</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">19457084</ArticleId><ArticleId IdType="pii">JNC6165</ArticleId><ArticleId IdType="doi">10.1111/j.1471-4159.2009.06165.x</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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