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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP</title><author><name sortKey="Haque, M Emdadul" sort="Haque, M Emdadul" uniqKey="Haque M" first="M. Emdadul" last="Haque">M. Emdadul Haque</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author><author><name sortKey="Thomas, Kelly J" sort="Thomas, Kelly J" uniqKey="Thomas K" first="Kelly J." last="Thomas">Kelly J. Thomas</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707;</nlm:aff></affiliation></author><author><name sortKey="D Souza, Cheryl" sort="D Souza, Cheryl" uniqKey="D Souza C" first="Cheryl" last="D'Souza">Cheryl D'Souza</name><affiliation><nlm:aff id="aff4">Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</nlm:aff></affiliation></author><author><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author><author><name sortKey="Kitada, Tohru" sort="Kitada, Tohru" uniqKey="Kitada T" first="Tohru" last="Kitada">Tohru Kitada</name><affiliation><nlm:aff wicri:cut="; and" id="aff3">Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115</nlm:aff></affiliation></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S." last="Slack">Ruth S. Slack</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name><affiliation><nlm:aff id="aff4">Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</nlm:aff></affiliation></author><author><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707;</nlm:aff></affiliation></author><author><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name><affiliation><nlm:aff id="aff4">Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</nlm:aff></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18218782</idno><idno type="pmc">2234210</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234210</idno><idno type="RBID">PMC:2234210</idno><idno type="doi">10.1073/pnas.0705363105</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">000661</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000661</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP</title><author><name sortKey="Haque, M Emdadul" sort="Haque, M Emdadul" uniqKey="Haque M" first="M. Emdadul" last="Haque">M. Emdadul Haque</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author><author><name sortKey="Thomas, Kelly J" sort="Thomas, Kelly J" uniqKey="Thomas K" first="Kelly J." last="Thomas">Kelly J. Thomas</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707;</nlm:aff></affiliation></author><author><name sortKey="D Souza, Cheryl" sort="D Souza, Cheryl" uniqKey="D Souza C" first="Cheryl" last="D'Souza">Cheryl D'Souza</name><affiliation><nlm:aff id="aff4">Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</nlm:aff></affiliation></author><author><name sortKey="Callaghan, Steve" sort="Callaghan, Steve" uniqKey="Callaghan S" first="Steve" last="Callaghan">Steve Callaghan</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author><author><name sortKey="Kitada, Tohru" sort="Kitada, Tohru" uniqKey="Kitada T" first="Tohru" last="Kitada">Tohru Kitada</name><affiliation><nlm:aff wicri:cut="; and" id="aff3">Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115</nlm:aff></affiliation></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S." last="Slack">Ruth S. Slack</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author><author><name sortKey="Fraser, Paul" sort="Fraser, Paul" uniqKey="Fraser P" first="Paul" last="Fraser">Paul Fraser</name><affiliation><nlm:aff id="aff4">Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</nlm:aff></affiliation></author><author><name sortKey="Cookson, Mark R" sort="Cookson, Mark R" uniqKey="Cookson M" first="Mark R." last="Cookson">Mark R. Cookson</name><affiliation><nlm:aff id="aff2">Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707;</nlm:aff></affiliation></author><author><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name><affiliation><nlm:aff id="aff4">Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</nlm:aff></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><affiliation><nlm:aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP<sup>+</sup>. Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both <italic>in vitro</italic> and <italic>in vivo</italic>. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP<sup>+</sup>)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18218782</article-id><article-id pub-id-type="pmc">2234210</article-id><article-id pub-id-type="publisher-id">9129</article-id><article-id pub-id-type="doi">10.1073/pnas.0705363105</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group></article-categories><title-group><article-title>Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Haque</surname><given-names>M. Emdadul</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Kelly J.</given-names></name><xref ref-type="aff" rid="aff2"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>D'Souza</surname><given-names>Cheryl</given-names></name><xref ref-type="aff" rid="aff4"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Callaghan</surname><given-names>Steve</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Kitada</surname><given-names>Tohru</given-names></name><xref ref-type="aff" rid="aff3"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Slack</surname><given-names>Ruth S.</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Fraser</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="aff4"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cookson</surname><given-names>Mark R.</given-names></name><xref ref-type="aff" rid="aff2"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tandon</surname><given-names>Anurag</given-names></name><xref ref-type="aff" rid="aff4"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>David S.</given-names></name><xref ref-type="aff" rid="aff1">*</xref><xref ref-type="corresp" rid="cor1"><sup>¶</sup></xref></contrib><aff id="aff1">*Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5;</aff><aff id="aff2"><sup>†</sup>Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707;</aff><aff id="aff3"><sup>§</sup>Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115; and</aff><aff id="aff4"><sup>‡</sup>Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen's Park Crescent West, Toronto, ON, Canada M5S 3H2</aff></contrib-group><author-notes><corresp id="cor1"><sup>¶</sup>To whom correspondence should be addressed. E-mail: <email>dpark@uottawa.ca</email></corresp><fn fn-type="edited-by"><p>Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved December 12, 2007</p></fn><fn fn-type="con"><p>Author contributions: A.T. and D.S.P. contributed equally to this work; M.E.H. and D.S.P. designed research; M.E.H., K.J.T., P.F., and M.R.C. performed research; K.J.T., C.D., S.C., T.K., R.S.S., M.R.C., and A.T. contributed new reagents/analytic tools; M.E.H., P.F., and D.S.P. analyzed data; and M.E.H. and D.S.P. wrote the paper.</p></fn></author-notes><pub-date pub-type="ppub"><day>5</day><month>2</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>24</day><month>1</month><year>2008</year></pub-date><volume>105</volume><issue>5</issue><fpage>1716</fpage><lpage>1721</lpage><history><date date-type="received"><day>7</day><month>6</month><year>2007</year></date></history><copyright-statement>© 2008 by The National Academy of Sciences of the USA</copyright-statement><copyright-year>2008</copyright-year><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zpq00508001716.pdf"></self-uri><abstract><p>PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP<sup>+</sup>. Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both <italic>in vitro</italic> and <italic>in vivo</italic>. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP<sup>+</sup>)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.</p></abstract><kwd-group><kwd>Parkinson's disease</kwd><kwd>neurodegeneration</kwd><kwd>neuroprotection</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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