RAPAMYCIN PROTECTS AGAINST ROTENONE-INDUCED APOPTOSIS THROUGH AUTOPHAGY INDUCTION
Identifieur interne : 000B27 ( Main/Exploration ); précédent : 000B26; suivant : 000B28RAPAMYCIN PROTECTS AGAINST ROTENONE-INDUCED APOPTOSIS THROUGH AUTOPHAGY INDUCTION
Auteurs : T Pan [États-Unis] ; P Rawal [États-Unis] ; Y Wu [États-Unis] ; W Xie [États-Unis] ; J Jankovic [États-Unis] ; W Le [États-Unis]Source :
- Neuroscience [ 0306-4522 ] ; 2009.
Descripteurs français
- Pascal (Inist)
English descriptors
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Abstract
Ubiquitin proteasome system (UPS) and autophagy lysosome pathway (ALP) are the two most important routes for degradation of aggregated/misfolded proteins. Additionally, ALP is so far the only known route to clear entire organelles, such as mitochondria. We proposed that enhancement of ALP may be beneficial for some neurodegenerative disorders, such as Parkinson's disease (PD), in which the accumulation of aggregated/misfolded proteins and the dysfunction of mitochondria are the two major pathogenesis. Mitochondrial complex I inhibitor rotenone, which causes dysfunction mitochondria and UPS, has been considered as one of the neurotoxins related to PD. In this study, rotenone-exposed human neuronal SH-SYSY cells were used as an in vitro model for us to determine whether autophagy enhancer rapamycin could protect against rotenone-induced injury and its underlying mechanisms. The observed results showed that rapamycin alleviated rotenone-induced apoptosis, whose effects were partially blocked when autophagy related gene 5 (Atg5) was suppressed by Atg5 small interference RNA (siRNA) transfection. Additionally, the results showed that rapamycin pretreatment diminished rotenone-induced accumulation of high molecular weight ubiquitinated bands, and reduced rotenone-induced increase of cytochrome c in cytosolic fraction and decreased mitochondrial marker cytochrome oxidase subunit IV (COX IV) in mitochondrial fraction. The changes in cytochrome c and COX IV indicated that the decreased translocation of cytochrome c from mitochondria to cytosol was probably due to the turn over of entire injured mitochondria. The results that lysosome and mitochondria were colocolized within the cells pretreated with rapamycin and that the mitochondria could be found within autophagy double membrane structures further supported that the damaged mitochondria might be cleared through autophagy, which process has been termed as "mitophagy." Our studies suggested that autophagy enhancer rapamycin is neuroprotective against rotenone-induced apoptosis through autophagy enhancement. We concluded that pharmacologically induction of autophagy by rapamycin may represent a useful therapeutic strategy as disease-modifiers in PD.
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aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Wu, Y" sort="Wu, Y" uniqKey="Wu Y" first="Y" last="Wu">Y Wu</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Parkinson's Disease Centre and Movement Disorder Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin Street, Suite 1801</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region 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sort="Rawal, P" uniqKey="Rawal P" first="P" last="Rawal">P Rawal</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Wu, Y" sort="Wu, Y" uniqKey="Wu Y" first="Y" last="Wu">Y Wu</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Parkinson's Disease Centre and Movement Disorder Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin Street, Suite 1801</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Xie, W" sort="Xie, W" uniqKey="Xie W" first="W" last="Xie">W Xie</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Jankovic, J" sort="Jankovic, J" uniqKey="Jankovic J" first="J" last="Jankovic">J Jankovic</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Parkinson's Disease Centre and Movement Disorder Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin Street, Suite 1801</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Le, W" sort="Le, W" uniqKey="Le W" first="W" last="Le">W Le</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, One Baylor Plaza</s1><s2>Houston 77030, TX</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Texas</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Neuroscience</title><title level="j" type="abbreviated">Neuroscience</title><idno type="ISSN">0306-4522</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Neuroscience</title><title level="j" type="abbreviated">Neuroscience</title><idno type="ISSN">0306-4522</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Apoptosis</term><term>Parkinson disease</term><term>Rotenone</term><term>Sirolimus</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Sirolimus</term><term>Apoptose</term><term>Maladie de Parkinson</term><term>Roténone</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Ubiquitin proteasome system (UPS) and autophagy lysosome pathway (ALP) are the two most important routes for degradation of aggregated/misfolded proteins. Additionally, ALP is so far the only known route to clear entire organelles, such as mitochondria. We proposed that enhancement of ALP may be beneficial for some neurodegenerative disorders, such as Parkinson's disease (PD), in which the accumulation of aggregated/misfolded proteins and the dysfunction of mitochondria are the two major pathogenesis. Mitochondrial complex I inhibitor rotenone, which causes dysfunction mitochondria and UPS, has been considered as one of the neurotoxins related to PD. In this study, rotenone-exposed human neuronal SH-SYSY cells were used as an in vitro model for us to determine whether autophagy enhancer rapamycin could protect against rotenone-induced injury and its underlying mechanisms. The observed results showed that rapamycin alleviated rotenone-induced apoptosis, whose effects were partially blocked when autophagy related gene 5 (Atg5) was suppressed by Atg5 small interference RNA (siRNA) transfection. Additionally, the results showed that rapamycin pretreatment diminished rotenone-induced accumulation of high molecular weight ubiquitinated bands, and reduced rotenone-induced increase of cytochrome c in cytosolic fraction and decreased mitochondrial marker cytochrome oxidase subunit IV (COX IV) in mitochondrial fraction. The changes in cytochrome c and COX IV indicated that the decreased translocation of cytochrome c from mitochondria to cytosol was probably due to the turn over of entire injured mitochondria. The results that lysosome and mitochondria were colocolized within the cells pretreated with rapamycin and that the mitochondria could be found within autophagy double membrane structures further supported that the damaged mitochondria might be cleared through autophagy, which process has been termed as "mitophagy." Our studies suggested that autophagy enhancer rapamycin is neuroprotective against rotenone-induced apoptosis through autophagy enhancement. We concluded that pharmacologically induction of autophagy by rapamycin may represent a useful therapeutic strategy as disease-modifiers in PD.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Texas</li></region></list><tree><country name="États-Unis"><region name="Texas"><name sortKey="Pan, T" sort="Pan, T" uniqKey="Pan T" first="T" last="Pan">T Pan</name></region><name sortKey="Jankovic, J" sort="Jankovic, J" uniqKey="Jankovic J" first="J" last="Jankovic">J Jankovic</name><name sortKey="Le, W" sort="Le, W" uniqKey="Le W" first="W" last="Le">W Le</name><name sortKey="Rawal, P" sort="Rawal, P" uniqKey="Rawal P" first="P" last="Rawal">P Rawal</name><name sortKey="Wu, Y" sort="Wu, Y" uniqKey="Wu Y" first="Y" last="Wu">Y Wu</name><name sortKey="Wu, Y" sort="Wu, Y" uniqKey="Wu Y" first="Y" last="Wu">Y Wu</name><name sortKey="Xie, W" sort="Xie, W" uniqKey="Xie W" first="W" last="Xie">W Xie</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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