Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death
Identifieur interne : 000178 ( France/Analysis ); précédent : 000177; suivant : 000179Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death
Auteurs : Fre De Ric Darios ; Olga Corti ; Christoph B. Lu Cking ; Cornelia Hampe ; Marie-Paule Muriel ; Nacer Abbas ; Wen-Jie Gu ; Etienne C. Hirsch ; Thomas Rooney [France] ; Merle Ruberg ; Alexis BriceSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2003-03-01.
Abstract
Parkin gene mutations have been implicated in autosomal-recessive early-onset parkinsonism and lead to specific degeneration of dopaminergic neurons in midbrain. To investigate the role of Parkin in neuronal cell death, we overproduced this protein in PC12 cells in an inducible manner. In this cell line, neuronally differentiated by nerve growth factor, Parkin overproduction protected against cell death mediated by ceramide, but not by a variety of other cell death inducers (H2O2, 4-hydroxynonenal, rotenone, 6-OHDA, tunicamycin, 2-mercaptoethanol and staurosporine). Protection was abrogated by the proteasome inhibitor epoxomicin and disease-causing variants, indicating that it was mediated by the E3 ubiquitin ligase activity of Parkin. Interestingly, Parkin acted by delaying mitochondrial swelling and subsequent cytochrome c release and caspase-3 activation observed in ceramide-mediated cell death. Subcellular fractionation demonstrated enrichment of Parkin in the mitochondrial fraction and its association with the outer mitochondrial membrane. Together, these results suggest that Parkin may promote the degradation of substrates localized in mitochondria and involved in the late mitochondrial phase of ceramide-mediated cell death. Loss of this function may underlie the degeneration of nigral dopaminergic neurons in patients with Parkin mutations.
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DOI: 10.1093/hmg/ddg044
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Mol. Genet.</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2003-03-01">2003-03-01</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="517">517</biblScope><biblScope unit="page" to="526">526</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">657759B8DA3EB71DB47D334186F46E0115B256A6</idno><idno type="DOI">10.1093/hmg/ddg044</idno><idno type="local">ddg044</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkin gene mutations have been implicated in autosomal-recessive early-onset parkinsonism and lead to specific degeneration of dopaminergic neurons in midbrain. To investigate the role of Parkin in neuronal cell death, we overproduced this protein in PC12 cells in an inducible manner. In this cell line, neuronally differentiated by nerve growth factor, Parkin overproduction protected against cell death mediated by ceramide, but not by a variety of other cell death inducers (H2O2, 4-hydroxynonenal, rotenone, 6-OHDA, tunicamycin, 2-mercaptoethanol and staurosporine). Protection was abrogated by the proteasome inhibitor epoxomicin and disease-causing variants, indicating that it was mediated by the E3 ubiquitin ligase activity of Parkin. Interestingly, Parkin acted by delaying mitochondrial swelling and subsequent cytochrome c release and caspase-3 activation observed in ceramide-mediated cell death. Subcellular fractionation demonstrated enrichment of Parkin in the mitochondrial fraction and its association with the outer mitochondrial membrane. Together, these results suggest that Parkin may promote the degradation of substrates localized in mitochondria and involved in the late mitochondrial phase of ceramide-mediated cell death. Loss of this function may underlie the degeneration of nigral dopaminergic neurons in patients with Parkin mutations.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Vitry-Sur-Seine</li></settlement></list><tree><noCountry><name sortKey="Abbas, Nacer" sort="Abbas, Nacer" uniqKey="Abbas N" first="Nacer" last="Abbas">Nacer Abbas</name><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name><name sortKey="Darios, Fre De Ric" sort="Darios, Fre De Ric" uniqKey="Darios F" first="Fre De Ric" last="Darios">Fre De Ric Darios</name><name sortKey="Gu, Wen Jie" sort="Gu, Wen Jie" uniqKey="Gu W" first="Wen-Jie" last="Gu">Wen-Jie Gu</name><name sortKey="Hampe, Cornelia" sort="Hampe, Cornelia" uniqKey="Hampe C" first="Cornelia" last="Hampe">Cornelia Hampe</name><name sortKey="Hirsch, Etienne C" sort="Hirsch, Etienne C" uniqKey="Hirsch E" first="Etienne C." last="Hirsch">Etienne C. Hirsch</name><name sortKey="Lu Cking, Christoph B" sort="Lu Cking, Christoph B" uniqKey="Lu Cking C" first="Christoph B." last="Lu Cking">Christoph B. Lu Cking</name><name sortKey="Muriel, Marie Paule" sort="Muriel, Marie Paule" uniqKey="Muriel M" first="Marie-Paule" last="Muriel">Marie-Paule Muriel</name><name sortKey="Ruberg, Merle" sort="Ruberg, Merle" uniqKey="Ruberg M" first="Merle" last="Ruberg">Merle Ruberg</name></noCountry><country name="France"><region name="Île-de-France"><name sortKey="Rooney, Thomas" sort="Rooney, Thomas" uniqKey="Rooney T" first="Thomas" last="Rooney">Thomas Rooney</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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