The C289G and C418R missense mutations cause rapid sequestration of human Parkin into insoluble aggregates.
Identifieur interne : 000405 ( Ncbi/Curation ); précédent : 000404; suivant : 000406The C289G and C418R missense mutations cause rapid sequestration of human Parkin into insoluble aggregates.
Auteurs : Wen-Jie Gu [France] ; Olga Corti ; Francisco Araujo ; Cornelia Hampe ; Sandrine Jacquier ; Christoph B. Lücking ; Nacer Abbas ; Charles Duyckaerts ; Thomas Rooney ; Laurent Pradier ; Merle Ruberg ; Alexis BriceSource :
- Neurobiology of disease [ 0969-9961 ] ; 2003.
English descriptors
- KwdEn :
- Animals, COS Cells, Cysteine Endopeptidases (metabolism), Humans, Inclusion Bodies (genetics), Inclusion Bodies (metabolism), Macromolecular Substances, Microtubules (metabolism), Multienzyme Complexes (metabolism), Mutation, Missense (genetics), Neurons (metabolism), Neurons (pathology), Parkinson Disease (genetics), Parkinson Disease (metabolism), Parkinson Disease (physiopathology), Proteasome Endopeptidase Complex, Protein Folding, Protein Structure, Tertiary (genetics), Protein Transport (physiology), Solubility, Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism), Ubiquitins (metabolism).
- MESH :
- chemical , genetics : Ubiquitin-Protein Ligases.
- chemical , metabolism : Cysteine Endopeptidases, Multienzyme Complexes, Ubiquitin-Protein Ligases, Ubiquitins.
- genetics : Inclusion Bodies, Mutation, Missense, Parkinson Disease, Protein Structure, Tertiary.
- metabolism : Inclusion Bodies, Microtubules, Neurons, Parkinson Disease.
- pathology : Neurons.
- physiology : Protein Transport.
- physiopathology : Parkinson Disease.
- Animals, COS Cells, Humans, Macromolecular Substances, Proteasome Endopeptidase Complex, Protein Folding, Solubility.
Abstract
Mutations in the parkin gene are responsible for autosomal recessive parkinsonism. The disease-linked missense mutations are highly concentrated in the RING-IBR-RING domains of Parkin. In this study, we investigated the consequences of several missense parkin gene mutations in cell culture. We have demonstrated that two of these mutations (C289G and C418R), which replace consensus cysteine residues in the RING domains, significantly decrease the solubility of Parkin in cells. Upon overexpression, the presumably misfolded proteins formed cytoplasmic aggregates that concentrated into large perinuclear inclusion bodies when proteasome activity was inhibited. This process required active microtubule-dependent retrograde transport, as previously reported for aggresome formation. These results provide information on the molecular basis of the loss of function caused by mutations of critical residues in Parkin. They also contribute to our understanding of the cellular mechanism underlying the aggregation of mutant Parkin.
PubMed: 14678753
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Lücking</name></author><author><name sortKey="Abbas, Nacer" sort="Abbas, Nacer" uniqKey="Abbas N" first="Nacer" last="Abbas">Nacer Abbas</name></author><author><name sortKey="Duyckaerts, Charles" sort="Duyckaerts, Charles" uniqKey="Duyckaerts C" first="Charles" last="Duyckaerts">Charles Duyckaerts</name></author><author><name sortKey="Rooney, Thomas" sort="Rooney, Thomas" uniqKey="Rooney T" first="Thomas" last="Rooney">Thomas Rooney</name></author><author><name sortKey="Pradier, Laurent" sort="Pradier, Laurent" uniqKey="Pradier L" first="Laurent" last="Pradier">Laurent Pradier</name></author><author><name sortKey="Ruberg, Merle" sort="Ruberg, Merle" uniqKey="Ruberg M" first="Merle" last="Ruberg">Merle Ruberg</name></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2003">2003</date><idno type="RBID">pubmed:14678753</idno><idno type="pmid">14678753</idno><idno type="wicri:Area/PubMed/Corpus">001065</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001065</idno><idno type="wicri:Area/PubMed/Curation">001024</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001024</idno><idno type="wicri:Area/PubMed/Checkpoint">001024</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001024</idno><idno type="wicri:Area/Ncbi/Merge">000405</idno><idno type="wicri:Area/Ncbi/Curation">000405</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">The C289G and C418R missense mutations cause rapid sequestration of human Parkin into insoluble aggregates.</title><author><name sortKey="Gu, Wen Jie" sort="Gu, Wen Jie" uniqKey="Gu W" first="Wen-Jie" last="Gu">Wen-Jie Gu</name><affiliation wicri:level="3"><nlm:affiliation>INSERM U 289, Hôpital de la Salpêtrière, 75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM U 289, Hôpital de la Salpêtrière, 75013 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Corti, Olga" sort="Corti, Olga" uniqKey="Corti O" first="Olga" last="Corti">Olga Corti</name></author><author><name sortKey="Araujo, Francisco" sort="Araujo, Francisco" uniqKey="Araujo F" first="Francisco" last="Araujo">Francisco Araujo</name></author><author><name sortKey="Hampe, Cornelia" sort="Hampe, Cornelia" uniqKey="Hampe C" first="Cornelia" last="Hampe">Cornelia Hampe</name></author><author><name sortKey="Jacquier, Sandrine" sort="Jacquier, Sandrine" uniqKey="Jacquier S" first="Sandrine" last="Jacquier">Sandrine Jacquier</name></author><author><name sortKey="Lucking, Christoph B" sort="Lucking, Christoph B" uniqKey="Lucking C" first="Christoph B" last="Lücking">Christoph B. Lücking</name></author><author><name sortKey="Abbas, Nacer" sort="Abbas, Nacer" uniqKey="Abbas N" first="Nacer" last="Abbas">Nacer Abbas</name></author><author><name sortKey="Duyckaerts, Charles" sort="Duyckaerts, Charles" uniqKey="Duyckaerts C" first="Charles" last="Duyckaerts">Charles Duyckaerts</name></author><author><name sortKey="Rooney, Thomas" sort="Rooney, Thomas" uniqKey="Rooney T" first="Thomas" last="Rooney">Thomas Rooney</name></author><author><name sortKey="Pradier, Laurent" sort="Pradier, Laurent" uniqKey="Pradier L" first="Laurent" last="Pradier">Laurent Pradier</name></author><author><name sortKey="Ruberg, Merle" sort="Ruberg, Merle" uniqKey="Ruberg M" first="Merle" last="Ruberg">Merle Ruberg</name></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name></author></analytic><series><title level="j">Neurobiology of disease</title><idno type="ISSN">0969-9961</idno><imprint><date when="2003" type="published">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>COS Cells</term><term>Cysteine Endopeptidases (metabolism)</term><term>Humans</term><term>Inclusion Bodies (genetics)</term><term>Inclusion Bodies (metabolism)</term><term>Macromolecular Substances</term><term>Microtubules (metabolism)</term><term>Multienzyme Complexes (metabolism)</term><term>Mutation, Missense (genetics)</term><term>Neurons (metabolism)</term><term>Neurons (pathology)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (metabolism)</term><term>Parkinson Disease (physiopathology)</term><term>Proteasome Endopeptidase Complex</term><term>Protein Folding</term><term>Protein Structure, Tertiary (genetics)</term><term>Protein Transport (physiology)</term><term>Solubility</term><term>Ubiquitin-Protein Ligases (genetics)</term><term>Ubiquitin-Protein Ligases (metabolism)</term><term>Ubiquitins (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Multienzyme Complexes</term><term>Ubiquitin-Protein Ligases</term><term>Ubiquitins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Inclusion Bodies</term><term>Mutation, Missense</term><term>Parkinson Disease</term><term>Protein Structure, Tertiary</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Inclusion Bodies</term><term>Microtubules</term><term>Neurons</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neurons</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Protein Transport</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>COS Cells</term><term>Humans</term><term>Macromolecular Substances</term><term>Proteasome Endopeptidase Complex</term><term>Protein Folding</term><term>Solubility</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the parkin gene are responsible for autosomal recessive parkinsonism. The disease-linked missense mutations are highly concentrated in the RING-IBR-RING domains of Parkin. In this study, we investigated the consequences of several missense parkin gene mutations in cell culture. We have demonstrated that two of these mutations (C289G and C418R), which replace consensus cysteine residues in the RING domains, significantly decrease the solubility of Parkin in cells. Upon overexpression, the presumably misfolded proteins formed cytoplasmic aggregates that concentrated into large perinuclear inclusion bodies when proteasome activity was inhibited. This process required active microtubule-dependent retrograde transport, as previously reported for aggresome formation. These results provide information on the molecular basis of the loss of function caused by mutations of critical residues in Parkin. They also contribute to our understanding of the cellular mechanism underlying the aggregation of mutant Parkin.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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