The Parkinson disease-associated A30P mutation stabilizes α-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells
Identifieur interne : 002062 ( Main/Exploration ); précédent : 002061; suivant : 002063The Parkinson disease-associated A30P mutation stabilizes α-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells
Auteurs : WEI SONG [Canada] ; Amar Patel [Canada] ; Hamid Y. Qureshi [Canada] ; DONG HAN [Canada] ; Hyman M. Schipper [Canada] ; Hemant K. Paudel [Canada]Source :
- Journal of neurochemistry [ 0022-3042 ] ; 2009.
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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 α-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 α-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of α-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 α-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of α-synuclein was almost completely restored. In contrast to the effect on α-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated α-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of α-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.
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Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Neurology and Neurosurgery, McGill University</s1><s2>Montreal, Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">09-0301664</idno><date when="2009">2009</date><idno type="stanalyst">PASCAL 09-0301664 INIST</idno><idno type="RBID">Pascal:09-0301664</idno><idno type="wicri:Area/PascalFrancis/Corpus">000535</idno><idno type="wicri:Area/PascalFrancis/Curation">000757</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000411</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000411</idno><idno type="wicri:doubleKey">0022-3042:2009:Wei Song:the:parkinson:disease</idno><idno type="wicri:Area/Main/Merge">002215</idno><idno type="wicri:Area/Main/Curation">002062</idno><idno type="wicri:Area/Main/Exploration">002062</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">The Parkinson disease-associated A30P mutation stabilizes α-synuclein against proteasomal degradation triggered by heme oxygenase-1 over-expression in human neuroblastoma cells</title><author><name sortKey="Wei Song" sort="Wei Song" uniqKey="Wei Song" last="Wei Song">WEI SONG</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Patel, Amar" sort="Patel, Amar" uniqKey="Patel A" first="Amar" last="Patel">Amar Patel</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Neurology and Neurosurgery, McGill University</s1><s2>Montreal, Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Qureshi, Hamid Y" sort="Qureshi, Hamid Y" uniqKey="Qureshi H" first="Hamid Y." last="Qureshi">Hamid Y. Qureshi</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Dong Han" sort="Dong Han" uniqKey="Dong Han" last="Dong Han">DONG HAN</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></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 wicri:level="1"><inist:fA14 i1="01"><s1>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Neurology and Neurosurgery, McGill University</s1><s2>Montreal, Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-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><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Montreal, Quebec</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Neurology and Neurosurgery, McGill University</s1><s2>Montreal, Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author></analytic><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="2009">2009</date></imprint></series></biblStruct></sourceDesc><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></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Activation</term><term>Alzheimer disease</term><term>Antagonist</term><term>Carbon monoxide</term><term>Heme</term><term>Human</term><term>Intracellular</term><term>Iron</term><term>Mutation</term><term>Neuroblastoma</term><term>Parkinson disease</term><term>Precursor</term><term>Stress</term><term>Tau protein</term><term>Treatment</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Mutation</term><term>Hème</term><term>Neuroblastome</term><term>Protéine tau</term><term>Intracellulaire</term><term>Fer</term><term>Monoxyde de carbone</term><term>Précurseur</term><term>Maladie de Parkinson</term><term>Stress</term><term>Traitement</term><term>Démence d'Alzheimer</term><term>Antagoniste</term><term>Activation</term><term>Homme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Fer</term><term>Homme</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 α-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 α-synuclein protein levels in human neuroblastoma M17 cells. When over-expression of HO-1 was silenced in HO-1 transfected cells, level of α-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 α-synuclein levels. Furthermore, when HO-1 over-expressing cells were treated with the proteosome inhibitors, lactacystin and MG132, level of α-synuclein was almost completely restored. In contrast to the effect on α-synuclein [wild-type (WT)] levels, HO-1 over-expression did not significantly impact PD-associated α-synuclein (A30P) levels in these cells. HO-1 also significantly reduced aggregation of α-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><affiliations><list><country><li>Canada</li></country><region><li>Québec</li></region><settlement><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Wei Song" sort="Wei Song" uniqKey="Wei Song" last="Wei Song">WEI SONG</name></noRegion><name sortKey="Dong Han" sort="Dong Han" uniqKey="Dong Han" last="Dong Han">DONG HAN</name><name sortKey="Patel, Amar" sort="Patel, Amar" uniqKey="Patel A" first="Amar" last="Patel">Amar Patel</name><name sortKey="Patel, Amar" sort="Patel, Amar" uniqKey="Patel A" first="Amar" last="Patel">Amar Patel</name><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name><name sortKey="Paudel, Hemant K" sort="Paudel, Hemant K" uniqKey="Paudel H" first="Hemant K." last="Paudel">Hemant K. Paudel</name><name sortKey="Qureshi, Hamid Y" sort="Qureshi, Hamid Y" uniqKey="Qureshi H" first="Hamid Y." last="Qureshi">Hamid Y. Qureshi</name><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name><name sortKey="Schipper, Hyman M" sort="Schipper, Hyman M" uniqKey="Schipper H" first="Hyman M." last="Schipper">Hyman M. Schipper</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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