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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo</title><author><name sortKey="Lohr, Kelly M" sort="Lohr, Kelly M" uniqKey="Lohr K" first="Kelly M." last="Lohr">Kelly M. Lohr</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Bernstein, Alison I" sort="Bernstein, Alison I" uniqKey="Bernstein A" first="Alison I." last="Bernstein">Alison I. Bernstein</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Stout, Kristen A" sort="Stout, Kristen A" uniqKey="Stout K" first="Kristen A." last="Stout">Kristen A. Stout</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Dunn, Amy R" sort="Dunn, Amy R" uniqKey="Dunn A" first="Amy R." last="Dunn">Amy R. Dunn</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Lazo, Carlos R" sort="Lazo, Carlos R" uniqKey="Lazo C" first="Carlos R." last="Lazo">Carlos R. Lazo</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Alter, Shawn P" sort="Alter, Shawn P" uniqKey="Alter S" first="Shawn P." last="Alter">Shawn P. Alter</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Wang, Minzheng" sort="Wang, Minzheng" uniqKey="Wang M" first="Minzheng" last="Wang">Minzheng Wang</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Li, Yingjie" sort="Li, Yingjie" uniqKey="Li Y" first="Yingjie" last="Li">Yingjie Li</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Fan, Xueliang" sort="Fan, Xueliang" uniqKey="Fan X" first="Xueliang" last="Fan">Xueliang Fan</name><affiliation><nlm:aff id="aff3">Department of Pharmacology,</nlm:aff></affiliation></author><author><name sortKey="Hess, Ellen J" sort="Hess, Ellen J" uniqKey="Hess E" first="Ellen J." last="Hess">Ellen J. Hess</name><affiliation><nlm:aff id="aff3">Department of Pharmacology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Neurology,</nlm:aff></affiliation></author><author><name sortKey="Yi, Hong" sort="Yi, Hong" uniqKey="Yi H" first="Hong" last="Yi">Hong Yi</name><affiliation><nlm:aff wicri:cut=", and" id="aff5">Robert P. Apkarian Integrated Electron Microscopy Core</nlm:aff></affiliation></author><author><name sortKey="Vecchio, Laura M" sort="Vecchio, Laura M" uniqKey="Vecchio L" first="Laura M." last="Vecchio">Laura M. Vecchio</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Pharmacology and Toxicology,<institution>University of Toronto</institution>, Toronto, ON,<country>Canada</country> M5S 1A8</nlm:aff></affiliation></author><author><name sortKey="Goldstein, David S" sort="Goldstein, David S" uniqKey="Goldstein D" first="David S." last="Goldstein">David S. Goldstein</name><affiliation><nlm:aff id="aff7"><institution>National Institute of Neurological Disorders and Stroke</institution>, Bethesda,<addr-line>MD</addr-line> 20824</nlm:aff></affiliation></author><author><name sortKey="Guillot, Thomas S" sort="Guillot, Thomas S" uniqKey="Guillot T" first="Thomas S." last="Guillot">Thomas S. Guillot</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Salahpour, Ali" sort="Salahpour, Ali" uniqKey="Salahpour A" first="Ali" last="Salahpour">Ali Salahpour</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Pharmacology and Toxicology,<institution>University of Toronto</institution>, Toronto, ON,<country>Canada</country> M5S 1A8</nlm:aff></affiliation></author><author><name sortKey="Miller, Gary W" sort="Miller, Gary W" uniqKey="Miller G" first="Gary W." last="Miller">Gary W. Miller</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Pharmacology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Neurology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Center for Neurodegenerative Diseases,<institution>Emory University</institution>, Atlanta,<addr-line>GA</addr-line> 30322;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24979780</idno><idno type="pmc">4103325</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103325</idno><idno type="RBID">PMC:4103325</idno><idno type="doi">10.1073/pnas.1402134111</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000672</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000672</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo</title><author><name sortKey="Lohr, Kelly M" sort="Lohr, Kelly M" uniqKey="Lohr K" first="Kelly M." last="Lohr">Kelly M. Lohr</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Bernstein, Alison I" sort="Bernstein, Alison I" uniqKey="Bernstein A" first="Alison I." last="Bernstein">Alison I. Bernstein</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Stout, Kristen A" sort="Stout, Kristen A" uniqKey="Stout K" first="Kristen A." last="Stout">Kristen A. Stout</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Dunn, Amy R" sort="Dunn, Amy R" uniqKey="Dunn A" first="Amy R." last="Dunn">Amy R. Dunn</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Lazo, Carlos R" sort="Lazo, Carlos R" uniqKey="Lazo C" first="Carlos R." last="Lazo">Carlos R. Lazo</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Alter, Shawn P" sort="Alter, Shawn P" uniqKey="Alter S" first="Shawn P." last="Alter">Shawn P. Alter</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Wang, Minzheng" sort="Wang, Minzheng" uniqKey="Wang M" first="Minzheng" last="Wang">Minzheng Wang</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Li, Yingjie" sort="Li, Yingjie" uniqKey="Li Y" first="Yingjie" last="Li">Yingjie Li</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Fan, Xueliang" sort="Fan, Xueliang" uniqKey="Fan X" first="Xueliang" last="Fan">Xueliang Fan</name><affiliation><nlm:aff id="aff3">Department of Pharmacology,</nlm:aff></affiliation></author><author><name sortKey="Hess, Ellen J" sort="Hess, Ellen J" uniqKey="Hess E" first="Ellen J." last="Hess">Ellen J. Hess</name><affiliation><nlm:aff id="aff3">Department of Pharmacology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Neurology,</nlm:aff></affiliation></author><author><name sortKey="Yi, Hong" sort="Yi, Hong" uniqKey="Yi H" first="Hong" last="Yi">Hong Yi</name><affiliation><nlm:aff wicri:cut=", and" id="aff5">Robert P. Apkarian Integrated Electron Microscopy Core</nlm:aff></affiliation></author><author><name sortKey="Vecchio, Laura M" sort="Vecchio, Laura M" uniqKey="Vecchio L" first="Laura M." last="Vecchio">Laura M. Vecchio</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Pharmacology and Toxicology,<institution>University of Toronto</institution>, Toronto, ON,<country>Canada</country> M5S 1A8</nlm:aff></affiliation></author><author><name sortKey="Goldstein, David S" sort="Goldstein, David S" uniqKey="Goldstein D" first="David S." last="Goldstein">David S. Goldstein</name><affiliation><nlm:aff id="aff7"><institution>National Institute of Neurological Disorders and Stroke</institution>, Bethesda,<addr-line>MD</addr-line> 20824</nlm:aff></affiliation></author><author><name sortKey="Guillot, Thomas S" sort="Guillot, Thomas S" uniqKey="Guillot T" first="Thomas S." last="Guillot">Thomas S. Guillot</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation></author><author><name sortKey="Salahpour, Ali" sort="Salahpour, Ali" uniqKey="Salahpour A" first="Ali" last="Salahpour">Ali Salahpour</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Department of Pharmacology and Toxicology,<institution>University of Toronto</institution>, Toronto, ON,<country>Canada</country> M5S 1A8</nlm:aff></affiliation></author><author><name sortKey="Miller, Gary W" sort="Miller, Gary W" uniqKey="Miller G" first="Gary W." last="Miller">Gary W. Miller</name><affiliation><nlm:aff id="aff1">Department of Environmental Health, Rollins School of Public Health,</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Department of Pharmacology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Department of Neurology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Center for Neurodegenerative Diseases,<institution>Emory University</institution>, Atlanta,<addr-line>GA</addr-line> 30322;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. However, many of these interventions have deleterious side effects or lose effectiveness due to off-target actions and system feedback. These undesirable consequences likely occur because of temporal dysregulation of neurotransmitter release and uptake. We demonstrate that increasing vesicular packaging enhances dopamine neurotransmission without this signaling disruption. Mice with elevated vesicular monoamine transporter display increased dopamine release, improved outcomes on anxiety and depressive behaviors, enhanced locomotion, and protection from a Parkinson disease-related neurotoxic insult. The malleable nature of the dopamine vesicle suggests that interventions aimed at enhancing vesicle filling may be of therapeutic benefit.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24979780</article-id><article-id pub-id-type="pmc">4103325</article-id><article-id pub-id-type="publisher-id">201402134</article-id><article-id pub-id-type="doi">10.1073/pnas.1402134111</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Pharmacology</subject></subj-group></subj-group></article-categories><title-group><article-title>Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo</article-title><alt-title alt-title-type="short">In vivo overexpression of VMAT2</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lohr</surname><given-names>Kelly M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bernstein</surname><given-names>Alison I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stout</surname><given-names>Kristen A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dunn</surname><given-names>Amy R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lazo</surname><given-names>Carlos R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Alter</surname><given-names>Shawn P.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Minzheng</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yingjie</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fan</surname><given-names>Xueliang</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hess</surname><given-names>Ellen J.</given-names></name><xref ref-type="aff" rid="aff3"><sup>b</sup></xref><xref ref-type="aff" rid="aff4"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yi</surname><given-names>Hong</given-names></name><xref ref-type="aff" rid="aff5"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vecchio</surname><given-names>Laura M.</given-names></name><xref ref-type="aff" rid="aff6"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Goldstein</surname><given-names>David S.</given-names></name><xref ref-type="aff" rid="aff7"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guillot</surname><given-names>Thomas S.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Salahpour</surname><given-names>Ali</given-names></name><xref ref-type="aff" rid="aff6"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Miller</surname><given-names>Gary W.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>b</sup></xref><xref ref-type="aff" rid="aff4"><sup>c</sup></xref><xref ref-type="aff" rid="aff2"><sup>g</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><sup>a</sup>Department of Environmental Health, Rollins School of Public Health,</aff><aff id="aff3"><sup>b</sup>Department of Pharmacology,</aff><aff id="aff4"><sup>c</sup>Department of Neurology,</aff><aff id="aff5"><sup>d</sup>Robert P. Apkarian Integrated Electron Microscopy Core, and</aff><aff id="aff2"><sup>g</sup>Center for Neurodegenerative Diseases,<institution>Emory University</institution>, Atlanta,<addr-line>GA</addr-line> 30322;</aff><aff id="aff6"><sup>e</sup>Department of Pharmacology and Toxicology,<institution>University of Toronto</institution>, Toronto, ON,<country>Canada</country> M5S 1A8; and</aff><aff id="aff7"><sup>f</sup><institution>National Institute of Neurological Disorders and Stroke</institution>, Bethesda,<addr-line>MD</addr-line> 20824</aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence should be addressed. E-mail: <email>gary.miller@emory.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by David Sulzer, College of Physicians and Surgeons, Columbia University, New York, NY, and accepted by the Editorial Board May 23, 2014 (received for review February 25, 2014)</p></fn><fn fn-type="con"><p>Author contributions: K.M.L., A.I.B., E.J.H., H.Y., T.S.G., and G.W.M. designed research; K.M.L., A.I.B., K.A.S., A.R.D., C.R.L., M.W., Y.L., X.F., H.Y., and L.M.V. performed research; X.F., E.J.H., H.Y., L.M.V., D.S.G., and A.S. contributed new reagents/analytic tools; K.M.L., A.I.B., K.A.S., A.R.D., C.R.L., S.P.A., Y.L., X.F., E.J.H., H.Y., L.M.V., D.S.G., T.S.G., and G.W.M. analyzed data; and K.M.L., A.I.B., and G.W.M. wrote the paper.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>K.M.L. and A.I.B. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>8</day><month>7</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>16</day><month>6</month><year>2014</year></pub-date><volume>111</volume><issue>27</issue><fpage>9977</fpage><lpage>9982</lpage><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201402134.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Several therapeutic strategies have been used to enhance monoamine neurotransmitter signaling. However, many of these interventions have deleterious side effects or lose effectiveness due to off-target actions and system feedback. These undesirable consequences likely occur because of temporal dysregulation of neurotransmitter release and uptake. We demonstrate that increasing vesicular packaging enhances dopamine neurotransmission without this signaling disruption. Mice with elevated vesicular monoamine transporter display increased dopamine release, improved outcomes on anxiety and depressive behaviors, enhanced locomotion, and protection from a Parkinson disease-related neurotoxic insult. The malleable nature of the dopamine vesicle suggests that interventions aimed at enhancing vesicle filling may be of therapeutic benefit.</p></abstract><abstract><p>Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; <italic>Slc18a2</italic>). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease.</p></abstract><kwd-group><kwd>SLC18A2</kwd><kwd>fast-scan cyclic voltammetry</kwd><kwd>serotonin</kwd><kwd>norepinephrine</kwd></kwd-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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