Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals
Identifieur interne : 001A84 ( Main/Corpus ); précédent : 001A83; suivant : 001A85Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals
Auteurs : Zhen Qi ; Gary W. Miller ; Eberhard O. VoitSource :
- Synapse [ 0887-4476 ] ; 2009-12.
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Abstract
Dopamine signaling is involved in a number of brain pathways, and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo‐ and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine‐based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. Synapse 63:1133–1142, 2009. © 2009 Wiley‐Liss, Inc.
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DOI: 10.1002/syn.20686
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It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo‐ and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine‐based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. Synapse 63:1133–1142, 2009. © 2009 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Zhen Qi</name><affiliations><json:string>Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA</json:string><json:string>Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA</json:string></affiliations></json:item><json:item><name>Gary W. Miller</name><affiliations><json:string>Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA</json:string><json:string>Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, GA</json:string></affiliations></json:item><json:item><name>Eberhard O. 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It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo‐ and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine‐based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. 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Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. 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O.</givenNames><familyName>Voit</familyName></personName><contactDetails><email>eberhard.voit@bme.gatech.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, GA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">Biochemical Systems Theory</keyword><keyword xml:id="kwd2">dopamine metabolism</keyword><keyword xml:id="kwd3">dopamine nerve terminal</keyword><keyword xml:id="kwd4">Monte Carlo method</keyword><keyword xml:id="kwd5">metabolic profile</keyword><keyword xml:id="kwd6">Parkinson's disease</keyword><keyword xml:id="kwd7">personalized medicine</keyword></keywordGroup><fundingInfo><fundingAgency>Woodruff Health Science Center Fund</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NIH</fundingAgency><fundingNumber>P01‐ES016731</fundingNumber><fundingNumber>U54‐ES012068</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Georgia Research Alliance</fundingAgency></fundingInfo><supportingInformation><p> Additional Supporting Information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:08874476:media:syn20686:SYN_20686_sm_suppinfofigure1"></mediaResource><caption>Figure S1. Graph of significant two‐site combinations for HO</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:08874476:media:syn20686:SYN_20686_sm_suppinfofigure2"></mediaResource><caption>Figure S2. Scatter plots of total dopamine, nitrogen dioxide, and dopac quinone in response to manipulations of MAO with VMAT2 and of COMT with DAT</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:08874476:media:syn20686:SYN_20686_sm_suppinfo"></mediaResource><caption>Supporting Information</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Dopamine signaling is involved in a number of brain pathways, and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo‐ and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine‐based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. Synapse 63:1133–1142, 2009. © 2009 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Computational Analysis of Determinants of Dopamine Dysfunction</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals</title></titleInfo><name type="personal"><namePart type="given">Zhen</namePart><namePart type="family">Qi</namePart><affiliation>Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA</affiliation><affiliation>Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gary W.</namePart><namePart type="family">Miller</namePart><affiliation>Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA</affiliation><affiliation>Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, GA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eberhard O.</namePart><namePart type="family">Voit</namePart><affiliation>Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA</affiliation><description>Correspondence: Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA 30332</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2009-12</dateIssued><dateCaptured encoding="w3cdtf">2008-10-21</dateCaptured><dateValid encoding="w3cdtf">2009-03-04</dateValid><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">5</extent><extent unit="references">32</extent><extent unit="words">848</extent></physicalDescription><abstract lang="en">Dopamine signaling is involved in a number of brain pathways, and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo‐ and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine‐based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. Synapse 63:1133–1142, 2009. © 2009 Wiley‐Liss, Inc.</abstract><note type="funding">Woodruff Health Science Center Fund</note><note type="funding">NIH - No. P01‐ES016731; No. U54‐ES012068; </note><note type="funding">Georgia Research Alliance</note><subject lang="en"><genre>Keywords</genre><topic>Biochemical Systems Theory</topic><topic>dopamine metabolism</topic><topic>dopamine nerve terminal</topic><topic>Monte Carlo method</topic><topic>metabolic profile</topic><topic>Parkinson's disease</topic><topic>personalized medicine</topic></subject><relatedItem type="host"><titleInfo><title>Synapse</title></titleInfo><titleInfo type="abbreviated"><title>Synapse</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Figure S1. Graph of significant two‐site combinations for HO - Figure S2. Scatter plots of total dopamine, nitrogen dioxide, and dopac quinone in response to manipulations of MAO with VMAT2 and of COMT with DAT - Supporting Information - </note><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0887-4476</identifier><identifier type="eISSN">1098-2396</identifier><identifier type="DOI">10.1002/(ISSN)1098-2396</identifier><identifier type="PublisherID">SYN</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>63</number></detail><detail type="issue"><caption>no.</caption><number>12</number></detail><extent unit="pages"><start>1133</start><end>1142</end><total>10</total></extent></part></relatedItem><identifier type="istex">4D8906CBF780D75F05A02C104E08EA32F5130E3D</identifier><identifier type="DOI">10.1002/syn.20686</identifier><identifier type="ArticleID">SYN20686</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2009 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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