Mutant torsinA, which causes early‐onset primary torsion dystonia, is redistributed to membranous structures enriched in vesicular monoamine transporter in cultured human SH‐SY5Y cells
Identifieur interne : 003835 ( Main/Exploration ); précédent : 003834; suivant : 003836Mutant torsinA, which causes early‐onset primary torsion dystonia, is redistributed to membranous structures enriched in vesicular monoamine transporter in cultured human SH‐SY5Y cells
Auteurs : Anjum Misbahuddin [Royaume-Uni] ; Mark R. Placzek [Royaume-Uni] ; Jan-Willem Taanman [Royaume-Uni] ; Steve Gschmeissner [Royaume-Uni] ; Giampietro Schiavo [Royaume-Uni] ; J. Mark Cooper [Royaume-Uni] ; Thomas T. Warner [Royaume-Uni]Source :
- Movement Disorders [ 0885-3185 ] ; 2005-04.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
- Age Factors, Blotting, Western, Cell Line, Tumor, Cell culture, DNA, Complementary (genetics), DYT1, Dystonia, Dystonia Musculorum Deformans (genetics), Dystonia Musculorum Deformans (metabolism), EM, Endoplasmic Reticulum (metabolism), Fluorescent Antibody Technique, Gene Deletion, Human, Humans, Membrane Glycoproteins (genetics), Membrane Glycoproteins (metabolism), Membrane Transport Proteins (genetics), Membrane Transport Proteins (metabolism), Microscopy, Electron, Molecular Chaperones (genetics), Molecular Chaperones (metabolism), Nervous system diseases, Neuroblastoma (genetics), Neuroblastoma (metabolism), Neuroblastoma (pathology), Point Mutation (genetics), Reverse Transcriptase Polymerase Chain Reaction, Torsion, Transfection, Trinucleotide Repeats (genetics), VMAT2, Vesicular Biogenic Amine Transport Proteins, Vesicular Monoamine Transport Proteins, Vesicular monoamine transporter, dystonia, torsinA.
- MESH :
- chemical , genetics : DNA, Complementary, Membrane Glycoproteins, Membrane Transport Proteins, Molecular Chaperones.
- genetics : Dystonia Musculorum Deformans, Neuroblastoma, Point Mutation, Trinucleotide Repeats.
- metabolism : Dystonia Musculorum Deformans, Endoplasmic Reticulum, Membrane Glycoproteins, Membrane Transport Proteins, Molecular Chaperones, Neuroblastoma.
- pathology : Neuroblastoma.
- Age Factors, Blotting, Western, Cell Line, Tumor, Fluorescent Antibody Technique, Gene Deletion, Humans, Microscopy, Electron, Reverse Transcriptase Polymerase Chain Reaction, Transfection, Vesicular Biogenic Amine Transport Proteins, Vesicular Monoamine Transport Proteins.
Abstract
A single GAG deletion in the DYT1 gene causes primary early‐onset, generalized torsion dystonia. The DYT1 protein product, torsinA, belongs to the AAA+ family of proteins. When overexpressed, wild‐type torsinA localizes mainly to the endoplasmic reticulum, whereas the mutant forms inclusions of unclear biogenetic origin. In this study, overexpressed wild‐type torsinA in human neuroblastoma (SH‐SY5Y) cell lines was distributed throughout the cell body and colocalized with a marker for the endoplasmic reticulum, confirming it is an endoplasmic reticulum protein. However, mutant torsinA showed perinuclear staining and formed distinct globular inclusions, which did not colocalize with endoplasmic reticulum markers. Immunoelectron microscopy of the mutant torsinA inclusions revealed membrane whorls staining for torsinA, as well as labeling of lamellae, isolated bilayers, and perinuclear membranes. This finding shows that mutant torsinA redistributes to specific membranous structures, which may represent different stages of maturation of the intracellular inclusions. The mutant torsinA‐containing bodies were immunoreactive for vesicular monoamine transporter 2 (VMAT2). VMAT2 expression is important for the exocytosis of bioactive monoamines in neurons. Abnormal processing, transport, or entrapment of VMAT2 within the mutant torsinA membranous inclusions, therefore, may affect cellular dopamine release, providing a potential pathogenic mechanism for the DYT1‐dependent dystonia. © 2004 Movement Disorder Society
Url:
DOI: 10.1002/mds.20351
Affiliations:
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Placzek</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences, Royal Free and University College Medical School, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Taanman, Jan Illem" sort="Taanman, Jan Illem" uniqKey="Taanman J" first="Jan-Willem" last="Taanman">Jan-Willem Taanman</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences, Royal Free and University College Medical School, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Gschmeissner, Steve" sort="Gschmeissner, Steve" uniqKey="Gschmeissner S" first="Steve" last="Gschmeissner">Steve Gschmeissner</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Schiavo, Giampietro" sort="Schiavo, Giampietro" uniqKey="Schiavo G" first="Giampietro" last="Schiavo">Giampietro Schiavo</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Cooper, J Mark" sort="Cooper, J Mark" uniqKey="Cooper J" first="J. Mark" last="Cooper">J. Mark Cooper</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences, Royal Free and University College Medical School, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Warner, Thomas T" sort="Warner, Thomas T" uniqKey="Warner T" first="Thomas T." last="Warner">Thomas T. Warner</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Clinical Neurosciences, Royal Free and University College Medical School, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2005-04">2005-04</date><biblScope unit="vol">20</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="432">432</biblScope><biblScope unit="page" to="440">440</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">2084E2E515DE8EAD1EE3DBBADBEBB7FDCDA735DD</idno><idno type="DOI">10.1002/mds.20351</idno><idno type="ArticleID">MDS20351</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Age Factors</term><term>Blotting, Western</term><term>Cell Line, Tumor</term><term>Cell culture</term><term>DNA, Complementary (genetics)</term><term>DYT1</term><term>Dystonia</term><term>Dystonia Musculorum Deformans (genetics)</term><term>Dystonia Musculorum Deformans (metabolism)</term><term>EM</term><term>Endoplasmic Reticulum (metabolism)</term><term>Fluorescent Antibody Technique</term><term>Gene Deletion</term><term>Human</term><term>Humans</term><term>Membrane Glycoproteins (genetics)</term><term>Membrane Glycoproteins (metabolism)</term><term>Membrane Transport Proteins (genetics)</term><term>Membrane Transport Proteins (metabolism)</term><term>Microscopy, Electron</term><term>Molecular Chaperones (genetics)</term><term>Molecular Chaperones (metabolism)</term><term>Nervous system diseases</term><term>Neuroblastoma (genetics)</term><term>Neuroblastoma (metabolism)</term><term>Neuroblastoma (pathology)</term><term>Point Mutation (genetics)</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Torsion</term><term>Transfection</term><term>Trinucleotide Repeats (genetics)</term><term>VMAT2</term><term>Vesicular Biogenic Amine Transport Proteins</term><term>Vesicular Monoamine Transport Proteins</term><term>Vesicular monoamine transporter</term><term>dystonia</term><term>torsinA</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>DNA, Complementary</term><term>Membrane Glycoproteins</term><term>Membrane Transport Proteins</term><term>Molecular Chaperones</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Dystonia Musculorum Deformans</term><term>Neuroblastoma</term><term>Point Mutation</term><term>Trinucleotide Repeats</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dystonia Musculorum Deformans</term><term>Endoplasmic Reticulum</term><term>Membrane Glycoproteins</term><term>Membrane Transport Proteins</term><term>Molecular Chaperones</term><term>Neuroblastoma</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Neuroblastoma</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Age Factors</term><term>Blotting, Western</term><term>Cell Line, Tumor</term><term>Fluorescent Antibody Technique</term><term>Gene Deletion</term><term>Humans</term><term>Microscopy, Electron</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Transfection</term><term>Vesicular Biogenic Amine Transport Proteins</term><term>Vesicular Monoamine Transport Proteins</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Culture cellulaire</term><term>Dystonie</term><term>Homme</term><term>Système nerveux pathologie</term><term>Torsion</term><term>Transporteur vésiculaire monoamine</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A single GAG deletion in the DYT1 gene causes primary early‐onset, generalized torsion dystonia. The DYT1 protein product, torsinA, belongs to the AAA+ family of proteins. When overexpressed, wild‐type torsinA localizes mainly to the endoplasmic reticulum, whereas the mutant forms inclusions of unclear biogenetic origin. In this study, overexpressed wild‐type torsinA in human neuroblastoma (SH‐SY5Y) cell lines was distributed throughout the cell body and colocalized with a marker for the endoplasmic reticulum, confirming it is an endoplasmic reticulum protein. However, mutant torsinA showed perinuclear staining and formed distinct globular inclusions, which did not colocalize with endoplasmic reticulum markers. Immunoelectron microscopy of the mutant torsinA inclusions revealed membrane whorls staining for torsinA, as well as labeling of lamellae, isolated bilayers, and perinuclear membranes. This finding shows that mutant torsinA redistributes to specific membranous structures, which may represent different stages of maturation of the intracellular inclusions. The mutant torsinA‐containing bodies were immunoreactive for vesicular monoamine transporter 2 (VMAT2). VMAT2 expression is important for the exocytosis of bioactive monoamines in neurons. Abnormal processing, transport, or entrapment of VMAT2 within the mutant torsinA membranous inclusions, therefore, may affect cellular dopamine release, providing a potential pathogenic mechanism for the DYT1‐dependent dystonia. © 2004 Movement Disorder Society</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Misbahuddin, Anjum" sort="Misbahuddin, Anjum" uniqKey="Misbahuddin A" first="Anjum" last="Misbahuddin">Anjum Misbahuddin</name></region><name sortKey="Cooper, J Mark" sort="Cooper, J Mark" uniqKey="Cooper J" first="J. Mark" last="Cooper">J. Mark Cooper</name><name sortKey="Gschmeissner, Steve" sort="Gschmeissner, Steve" uniqKey="Gschmeissner S" first="Steve" last="Gschmeissner">Steve Gschmeissner</name><name sortKey="Placzek, Mark R" sort="Placzek, Mark R" uniqKey="Placzek M" first="Mark R." last="Placzek">Mark R. Placzek</name><name sortKey="Schiavo, Giampietro" sort="Schiavo, Giampietro" uniqKey="Schiavo G" first="Giampietro" last="Schiavo">Giampietro Schiavo</name><name sortKey="Taanman, Jan Illem" sort="Taanman, Jan Illem" uniqKey="Taanman J" first="Jan-Willem" last="Taanman">Jan-Willem Taanman</name><name sortKey="Warner, Thomas T" sort="Warner, Thomas T" uniqKey="Warner T" first="Thomas T." last="Warner">Thomas T. Warner</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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