Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations.
Identifieur interne : 002948 ( Main/Exploration ); précédent : 002947; suivant : 002949Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations.
Auteurs : Agnes Petit [Canada] ; Toshitaka Kawarai ; Erwan Paitel ; Nobuo Sanjo ; Mary Maj ; Michael Scheid ; Fusheng Chen ; Yongjun Gu ; Hiroshi Hasegawa ; Shabnam Salehi-Rad ; Linda Wang ; Ekaterina Rogaeva ; Paul Fraser ; Brian Robinson ; Peter St George-Hyslop ; Anurag TandonSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2005.
English descriptors
- KwdEn :
- Aged, Amino Acid Sequence, Apoptosis (genetics), Caspase 3, Caspases (metabolism), Cell Culture Techniques, Cell Line, Cytochromes c (metabolism), DNA Mutational Analysis, Fibroblasts, Gene Expression Profiling, Humans, Male, Mitochondria (metabolism), Molecular Sequence Data, Neurons (physiology), Parkinson Disease (genetics), Parkinson Disease (pathology), Parkinson Disease (physiopathology), Phenotype, Protein Kinases (genetics), Protein Kinases (physiology), Receptors, Dopamine (physiology), Reverse Transcriptase Polymerase Chain Reaction.
- MESH :
- chemical , genetics : Protein Kinases.
- chemical , metabolism : Caspases, Cytochromes c.
- chemical , physiology : Protein Kinases, Receptors, Dopamine.
- chemical : Caspase 3.
- genetics : Apoptosis, Parkinson Disease.
- metabolism : Mitochondria.
- pathology : Parkinson Disease.
- physiology : Neurons.
- physiopathology : Parkinson Disease.
- Aged, Amino Acid Sequence, Cell Culture Techniques, Cell Line, DNA Mutational Analysis, Fibroblasts, Gene Expression Profiling, Humans, Male, Molecular Sequence Data, Phenotype, Reverse Transcriptase Polymerase Chain Reaction.
Abstract
Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations.
DOI: 10.1074/jbc.M505143200
PubMed: 16079129
Affiliations:
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uniqKey="Kawarai T" first="Toshitaka" last="Kawarai">Toshitaka Kawarai</name></author><author><name sortKey="Paitel, Erwan" sort="Paitel, Erwan" uniqKey="Paitel E" first="Erwan" last="Paitel">Erwan Paitel</name></author><author><name sortKey="Sanjo, Nobuo" sort="Sanjo, Nobuo" uniqKey="Sanjo N" first="Nobuo" last="Sanjo">Nobuo Sanjo</name></author><author><name sortKey="Maj, Mary" sort="Maj, Mary" uniqKey="Maj M" first="Mary" last="Maj">Mary Maj</name></author><author><name sortKey="Scheid, Michael" sort="Scheid, Michael" uniqKey="Scheid M" first="Michael" last="Scheid">Michael Scheid</name></author><author><name sortKey="Chen, Fusheng" sort="Chen, Fusheng" uniqKey="Chen F" first="Fusheng" last="Chen">Fusheng Chen</name></author><author><name sortKey="Gu, Yongjun" sort="Gu, Yongjun" uniqKey="Gu Y" first="Yongjun" last="Gu">Yongjun Gu</name></author><author><name sortKey="Hasegawa, Hiroshi" sort="Hasegawa, Hiroshi" uniqKey="Hasegawa H" first="Hiroshi" last="Hasegawa">Hiroshi Hasegawa</name></author><author><name sortKey="Salehi Rad, Shabnam" sort="Salehi Rad, Shabnam" uniqKey="Salehi Rad S" first="Shabnam" last="Salehi-Rad">Shabnam Salehi-Rad</name></author><author><name sortKey="Wang, Linda" sort="Wang, Linda" uniqKey="Wang L" first="Linda" last="Wang">Linda Wang</name></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name></author><author><name sortKey="Robinson, Brian" sort="Robinson, Brian" uniqKey="Robinson B" first="Brian" last="Robinson">Brian Robinson</name></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></author><author><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon 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type="wicri:Area/Main/Curation">002948</idno><idno type="wicri:Area/Main/Exploration">002948</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations.</title><author><name sortKey="Petit, Agnes" sort="Petit, Agnes" uniqKey="Petit A" first="Agnes" last="Petit">Agnes Petit</name><affiliation wicri:level="4"><nlm:affiliation>Centre for Research in Neurodegenerative Diseases, Department of Medicine (Neurology), University of Toronto, Toronto, Ontario M5S 3H2, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Research in Neurodegenerative Diseases, Department of Medicine (Neurology), University of Toronto, Toronto, Ontario M5S 3H2</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Kawarai, Toshitaka" sort="Kawarai, Toshitaka" uniqKey="Kawarai T" first="Toshitaka" last="Kawarai">Toshitaka Kawarai</name></author><author><name sortKey="Paitel, Erwan" sort="Paitel, Erwan" uniqKey="Paitel E" first="Erwan" last="Paitel">Erwan Paitel</name></author><author><name sortKey="Sanjo, Nobuo" sort="Sanjo, Nobuo" uniqKey="Sanjo N" first="Nobuo" last="Sanjo">Nobuo Sanjo</name></author><author><name sortKey="Maj, Mary" sort="Maj, Mary" uniqKey="Maj M" first="Mary" last="Maj">Mary Maj</name></author><author><name sortKey="Scheid, Michael" sort="Scheid, Michael" uniqKey="Scheid M" first="Michael" last="Scheid">Michael Scheid</name></author><author><name sortKey="Chen, Fusheng" sort="Chen, Fusheng" uniqKey="Chen F" first="Fusheng" last="Chen">Fusheng Chen</name></author><author><name sortKey="Gu, Yongjun" sort="Gu, Yongjun" uniqKey="Gu Y" first="Yongjun" last="Gu">Yongjun Gu</name></author><author><name sortKey="Hasegawa, Hiroshi" sort="Hasegawa, Hiroshi" uniqKey="Hasegawa H" first="Hiroshi" last="Hasegawa">Hiroshi Hasegawa</name></author><author><name sortKey="Salehi Rad, Shabnam" sort="Salehi Rad, Shabnam" uniqKey="Salehi Rad S" first="Shabnam" last="Salehi-Rad">Shabnam Salehi-Rad</name></author><author><name sortKey="Wang, Linda" sort="Wang, Linda" uniqKey="Wang L" first="Linda" last="Wang">Linda Wang</name></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name></author><author><name sortKey="Robinson, Brian" sort="Robinson, Brian" uniqKey="Robinson B" first="Brian" last="Robinson">Brian Robinson</name></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></author><author><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="ISSN">0021-9258</idno><imprint><date when="2005" type="published">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term><term>Amino Acid Sequence</term><term>Apoptosis (genetics)</term><term>Caspase 3</term><term>Caspases (metabolism)</term><term>Cell Culture Techniques</term><term>Cell Line</term><term>Cytochromes c (metabolism)</term><term>DNA Mutational Analysis</term><term>Fibroblasts</term><term>Gene Expression Profiling</term><term>Humans</term><term>Male</term><term>Mitochondria (metabolism)</term><term>Molecular Sequence Data</term><term>Neurons (physiology)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (pathology)</term><term>Parkinson Disease (physiopathology)</term><term>Phenotype</term><term>Protein Kinases (genetics)</term><term>Protein Kinases (physiology)</term><term>Receptors, Dopamine (physiology)</term><term>Reverse Transcriptase Polymerase Chain Reaction</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Protein Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Caspases</term><term>Cytochromes c</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Protein Kinases</term><term>Receptors, Dopamine</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Caspase 3</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Apoptosis</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Mitochondria</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Neurons</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Amino Acid Sequence</term><term>Cell Culture Techniques</term><term>Cell Line</term><term>DNA Mutational Analysis</term><term>Fibroblasts</term><term>Gene Expression Profiling</term><term>Humans</term><term>Male</term><term>Molecular Sequence Data</term><term>Phenotype</term><term>Reverse Transcriptase Polymerase Chain Reaction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="Chen, Fusheng" sort="Chen, Fusheng" uniqKey="Chen F" first="Fusheng" last="Chen">Fusheng Chen</name><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name><name sortKey="Gu, Yongjun" sort="Gu, Yongjun" uniqKey="Gu Y" first="Yongjun" last="Gu">Yongjun Gu</name><name sortKey="Hasegawa, Hiroshi" sort="Hasegawa, Hiroshi" uniqKey="Hasegawa H" first="Hiroshi" last="Hasegawa">Hiroshi Hasegawa</name><name sortKey="Kawarai, Toshitaka" sort="Kawarai, Toshitaka" uniqKey="Kawarai T" first="Toshitaka" last="Kawarai">Toshitaka Kawarai</name><name sortKey="Maj, Mary" sort="Maj, Mary" uniqKey="Maj M" first="Mary" last="Maj">Mary Maj</name><name sortKey="Paitel, Erwan" sort="Paitel, Erwan" uniqKey="Paitel E" first="Erwan" last="Paitel">Erwan Paitel</name><name sortKey="Robinson, Brian" sort="Robinson, Brian" uniqKey="Robinson B" first="Brian" last="Robinson">Brian Robinson</name><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><name sortKey="Salehi Rad, Shabnam" sort="Salehi Rad, Shabnam" uniqKey="Salehi Rad S" first="Shabnam" last="Salehi-Rad">Shabnam Salehi-Rad</name><name sortKey="Sanjo, Nobuo" sort="Sanjo, Nobuo" uniqKey="Sanjo N" first="Nobuo" last="Sanjo">Nobuo Sanjo</name><name sortKey="Scheid, Michael" sort="Scheid, Michael" uniqKey="Scheid M" first="Michael" last="Scheid">Michael Scheid</name><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name><name sortKey="Wang, Linda" sort="Wang, Linda" uniqKey="Wang L" first="Linda" last="Wang">Linda Wang</name></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Petit, Agnes" sort="Petit, Agnes" uniqKey="Petit A" first="Agnes" last="Petit">Agnes Petit</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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