Is Parkinson's disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum.
Identifieur interne : 000A22 ( Main/Exploration ); précédent : 000A21; suivant : 000A23Is Parkinson's disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum.
Auteurs : Christian Pifl [Autriche] ; Alex Rajput [Canada] ; Harald Reither [Autriche] ; Javier Blesa ; Carmen Cavada [Espagne] ; José A. Obeso ; Ali H. Rajput [Canada] ; Oleh Hornykiewicz [Autriche]Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience [ 1529-2401 ] ; 2014.
English descriptors
- KwdEn :
- Aged, Aged, 80 and over, Animals, Corpus Striatum (pathology), Corpus Striatum (ultrastructure), Disease Models, Animal, Dopamine (metabolism), Dopamine Uptake Inhibitors (pharmacokinetics), Female, Homovanillic Acid (metabolism), Humans, MPTP Poisoning (pathology), Macaca fascicularis, Male, Parkinson Disease (pathology), Synaptic Vesicles (metabolism), Tetrabenazine (analogs & derivatives), Tetrabenazine (pharmacokinetics), Tritium (metabolism), Tritium (pharmacokinetics), Vesicular Monoamine Transport Proteins (metabolism).
- MESH :
- chemical , analogs & derivatives : Tetrabenazine.
- chemical , metabolism : Dopamine, Homovanillic Acid, Tritium, Vesicular Monoamine Transport Proteins.
- metabolism : Synaptic Vesicles.
- pathology : Corpus Striatum, MPTP Poisoning, Parkinson Disease.
- chemical , pharmacokinetics : Dopamine Uptake Inhibitors, Tetrabenazine, Tritium.
- ultrastructure : Corpus Striatum.
- Aged, Aged, 80 and over, Animals, Disease Models, Animal, Female, Humans, Macaca fascicularis, Male.
Abstract
The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [(3)H]dihydrotetrabenazine were profoundly reduced in PD by 87-90% and 71-80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.
DOI: 10.1523/JNEUROSCI.5456-13.2014
PubMed: 24920625
Affiliations:
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Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum.</title><author><name sortKey="Pifl, Christian" sort="Pifl, Christian" uniqKey="Pifl C" first="Christian" last="Pifl">Christian Pifl</name><affiliation wicri:level="1"><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, christian.pifl@meduniwien.ac.at.</nlm:affiliation><country wicri:rule="url">Autriche</country><wicri:regionArea>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria</wicri:regionArea><wicri:noRegion>Austria</wicri:noRegion></affiliation></author><author><name sortKey="Rajput, Alex" sort="Rajput, Alex" uniqKey="Rajput A" first="Alex" last="Rajput">Alex Rajput</name><affiliation wicri:level="1"><nlm:affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8</wicri:regionArea><wicri:noRegion>SK S7N OW8</wicri:noRegion></affiliation></author><author><name sortKey="Reither, Harald" sort="Reither, Harald" uniqKey="Reither H" first="Harald" last="Reither">Harald Reither</name><affiliation wicri:level="1"><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Center for Brain Research, Medical University of Vienna, A-1090 Vienna</wicri:regionArea><wicri:noRegion>A-1090 Vienna</wicri:noRegion></affiliation></author><author><name sortKey="Blesa, Javier" sort="Blesa, Javier" uniqKey="Blesa J" first="Javier" last="Blesa">Javier Blesa</name><affiliation><nlm:affiliation>Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, Spain, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Cavada, Carmen" sort="Cavada, Carmen" uniqKey="Cavada C" first="Carmen" last="Cavada">Carmen Cavada</name><affiliation wicri:level="4"><nlm:affiliation>Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, E28049 Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, E28049 Madrid</wicri:regionArea><orgName type="university">Université autonome de Madrid</orgName><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Obeso, Jose A" sort="Obeso, Jose A" uniqKey="Obeso J" first="José A" last="Obeso">José A. Obeso</name><affiliation><nlm:affiliation>Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, Spain, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Rajput, Ali H" sort="Rajput, Ali H" uniqKey="Rajput A" first="Ali H" last="Rajput">Ali H. Rajput</name><affiliation wicri:level="1"><nlm:affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8</wicri:regionArea><wicri:noRegion>SK S7N OW8</wicri:noRegion></affiliation></author><author><name sortKey="Hornykiewicz, Oleh" sort="Hornykiewicz, Oleh" uniqKey="Hornykiewicz O" first="Oleh" last="Hornykiewicz">Oleh Hornykiewicz</name><affiliation wicri:level="1"><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</nlm:affiliation><country xml:lang="fr">Autriche</country><wicri:regionArea>Center for Brain Research, Medical University of Vienna, A-1090 Vienna</wicri:regionArea><wicri:noRegion>A-1090 Vienna</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of neuroscience : the official journal of the Society for Neuroscience</title><idno type="eISSN">1529-2401</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Corpus Striatum (pathology)</term><term>Corpus Striatum (ultrastructure)</term><term>Disease Models, Animal</term><term>Dopamine (metabolism)</term><term>Dopamine Uptake Inhibitors (pharmacokinetics)</term><term>Female</term><term>Homovanillic Acid (metabolism)</term><term>Humans</term><term>MPTP Poisoning (pathology)</term><term>Macaca fascicularis</term><term>Male</term><term>Parkinson Disease (pathology)</term><term>Synaptic Vesicles (metabolism)</term><term>Tetrabenazine (analogs & derivatives)</term><term>Tetrabenazine (pharmacokinetics)</term><term>Tritium (metabolism)</term><term>Tritium (pharmacokinetics)</term><term>Vesicular Monoamine Transport Proteins (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Tetrabenazine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term><term>Homovanillic Acid</term><term>Tritium</term><term>Vesicular Monoamine Transport Proteins</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Synaptic Vesicles</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Corpus Striatum</term><term>MPTP Poisoning</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Dopamine Uptake Inhibitors</term><term>Tetrabenazine</term><term>Tritium</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Corpus Striatum</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Humans</term><term>Macaca fascicularis</term><term>Male</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [(3)H]dihydrotetrabenazine were profoundly reduced in PD by 87-90% and 71-80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.</div></front></TEI><affiliations><list><country><li>Autriche</li><li>Canada</li><li>Espagne</li></country><region><li>Communauté de Madrid</li></region><settlement><li>Madrid</li></settlement><orgName><li>Université autonome de Madrid</li></orgName></list><tree><noCountry><name sortKey="Blesa, Javier" sort="Blesa, Javier" uniqKey="Blesa J" first="Javier" last="Blesa">Javier Blesa</name><name sortKey="Obeso, Jose A" sort="Obeso, Jose A" uniqKey="Obeso J" first="José A" last="Obeso">José A. Obeso</name></noCountry><country name="Autriche"><noRegion><name sortKey="Pifl, Christian" sort="Pifl, Christian" uniqKey="Pifl C" first="Christian" last="Pifl">Christian Pifl</name></noRegion><name sortKey="Hornykiewicz, Oleh" sort="Hornykiewicz, Oleh" uniqKey="Hornykiewicz O" first="Oleh" last="Hornykiewicz">Oleh Hornykiewicz</name><name sortKey="Reither, Harald" sort="Reither, Harald" uniqKey="Reither H" first="Harald" last="Reither">Harald Reither</name></country><country name="Canada"><noRegion><name sortKey="Rajput, Alex" sort="Rajput, Alex" uniqKey="Rajput A" first="Alex" last="Rajput">Alex Rajput</name></noRegion><name sortKey="Rajput, Ali H" sort="Rajput, Ali H" uniqKey="Rajput A" first="Ali H" last="Rajput">Ali H. Rajput</name></country><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Cavada, Carmen" sort="Cavada, Carmen" uniqKey="Cavada C" first="Carmen" last="Cavada">Carmen Cavada</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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