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 : 000731 ( PubMed/Corpus ); précédent : 000730; suivant : 000732Is 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 ; Alex Rajput ; Harald Reither ; Javier Blesa ; Carmen Cavada ; José A. Obeso ; Ali H. Rajput ; Oleh HornykiewiczSource :
- 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
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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><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, christian.pifl@meduniwien.ac.at.</nlm:affiliation></affiliation></author><author><name sortKey="Rajput, Alex" sort="Rajput, Alex" uniqKey="Rajput A" first="Alex" last="Rajput">Alex Rajput</name><affiliation><nlm:affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Reither, Harald" sort="Reither, Harald" uniqKey="Reither H" first="Harald" last="Reither">Harald Reither</name><affiliation><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</nlm:affiliation></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></affiliation></author><author><name sortKey="Cavada, Carmen" sort="Cavada, Carmen" uniqKey="Cavada C" first="Carmen" last="Cavada">Carmen Cavada</name><affiliation><nlm:affiliation>Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, E28049 Madrid, Spain.</nlm:affiliation></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></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><nlm:affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Hornykiewicz, Oleh" sort="Hornykiewicz, Oleh" uniqKey="Hornykiewicz O" first="Oleh" last="Hornykiewicz">Oleh Hornykiewicz</name><affiliation><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24920625</idno><idno type="pmid">24920625</idno><idno type="doi">10.1523/JNEUROSCI.5456-13.2014</idno><idno type="wicri:Area/PubMed/Corpus">000731</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000731</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Is Parkinson's disease a vesicular dopamine storage disorder? 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><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, christian.pifl@meduniwien.ac.at.</nlm:affiliation></affiliation></author><author><name sortKey="Rajput, Alex" sort="Rajput, Alex" uniqKey="Rajput A" first="Alex" last="Rajput">Alex Rajput</name><affiliation><nlm:affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Reither, Harald" sort="Reither, Harald" uniqKey="Reither H" first="Harald" last="Reither">Harald Reither</name><affiliation><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</nlm:affiliation></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></affiliation></author><author><name sortKey="Cavada, Carmen" sort="Cavada, Carmen" uniqKey="Cavada C" first="Carmen" last="Cavada">Carmen Cavada</name><affiliation><nlm:affiliation>Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, E28049 Madrid, Spain.</nlm:affiliation></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></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><nlm:affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Hornykiewicz, Oleh" sort="Hornykiewicz, Oleh" uniqKey="Hornykiewicz O" first="Oleh" last="Hornykiewicz">Oleh Hornykiewicz</name><affiliation><nlm:affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</nlm:affiliation></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24920625</PMID><DateCreated><Year>2014</Year><Month>06</Month><Day>12</Day></DateCreated><DateCompleted><Year>2014</Year><Month>08</Month><Day>04</Day></DateCompleted><DateRevised><Year>2016</Year><Month>03</Month><Day>04</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1529-2401</ISSN><JournalIssue CitedMedium="Internet"><Volume>34</Volume><Issue>24</Issue><PubDate><Year>2014</Year><Month>Jun</Month><Day>11</Day></PubDate></JournalIssue><Title>The Journal of neuroscience : the official journal of the Society for Neuroscience</Title><ISOAbbreviation>J. Neurosci.</ISOAbbreviation></Journal><ArticleTitle>Is Parkinson's disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum.</ArticleTitle><Pagination><MedlinePgn>8210-8</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1523/JNEUROSCI.5456-13.2014</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2014 the authors 0270-6474/14/348210-09$15.00/0.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pifl</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, christian.pifl@meduniwien.ac.at.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rajput</LastName><ForeName>Alex</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reither</LastName><ForeName>Harald</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blesa</LastName><ForeName>Javier</ForeName><Initials>J</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4257-1325</Identifier><AffiliationInfo><Affiliation>Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, Spain, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cavada</LastName><ForeName>Carmen</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, E28049 Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Obeso</LastName><ForeName>José A</ForeName><Initials>JA</Initials><AffiliationInfo><Affiliation>Movement Disorders Group, Neurosciences Division, CIMA, and Department of Neurology and Neurosurgery, Clinica Universidad de Navarra, E31008 Pamplona, Spain, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rajput</LastName><ForeName>Ali H</ForeName><Initials>AH</Initials><AffiliationInfo><Affiliation>Movement Disorders Program Saskatchewan, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, SK S7N OW8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hornykiewicz</LastName><ForeName>Oleh</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Neurosci</MedlineTA><NlmUniqueID>8102140</NlmUniqueID><ISSNLinking>0270-6474</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018765">Dopamine Uptake Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C493453">Slc18a2 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D050493">Vesicular Monoamine Transport Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>10028-17-8</RegistryNumber><NameOfSubstance UI="D014316">Tritium</NameOfSubstance></Chemical><Chemical><RegistryNumber>3466-75-9</RegistryNumber><NameOfSubstance UI="C032811">dihydrotetrabenazine</NameOfSubstance></Chemical><Chemical><RegistryNumber>VTD58H1Z2X</RegistryNumber><NameOfSubstance UI="D004298">Dopamine</NameOfSubstance></Chemical><Chemical><RegistryNumber>X77S6GMS36</RegistryNumber><NameOfSubstance UI="D006719">Homovanillic Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>Z9O08YRN8O</RegistryNumber><NameOfSubstance UI="D013747">Tetrabenazine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="ErratumIn"><RefSource>J Neurosci. 2015 Nov 25;35(47):15767</RefSource></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000369" MajorTopicYN="N">Aged, 80 and over</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003342" MajorTopicYN="N">Corpus Striatum</DescriptorName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName><QualifierName UI="Q000648" MajorTopicYN="Y">ultrastructure</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004195" MajorTopicYN="N">Disease Models, Animal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004298" MajorTopicYN="N">Dopamine</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018765" MajorTopicYN="N">Dopamine Uptake Inhibitors</DescriptorName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006719" MajorTopicYN="N">Homovanillic Acid</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020267" MajorTopicYN="N">MPTP Poisoning</DescriptorName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008252" MajorTopicYN="N">Macaca fascicularis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010300" MajorTopicYN="N">Parkinson Disease</DescriptorName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013572" MajorTopicYN="N">Synaptic Vesicles</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013747" MajorTopicYN="N">Tetrabenazine</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="N">analogs & derivatives</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014316" MajorTopicYN="N">Tritium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D050493" MajorTopicYN="N">Vesicular Monoamine Transport Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Parkinson's disease</Keyword><Keyword MajorTopicYN="N">VMAT2</Keyword><Keyword MajorTopicYN="N">dopamine</Keyword><Keyword MajorTopicYN="N">striatum</Keyword><Keyword MajorTopicYN="N">synaptic vesicles</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>6</Month><Day>13</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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