Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease.
Identifieur interne : 000089 ( PubMed/Corpus ); précédent : 000088; suivant : 000090Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease.
Auteurs : Wenjie Xie ; Xuping Li ; Chao Li ; Wen Zhu ; Joseph Jankovic ; Weidong LeSource :
- Journal of neurochemistry ; 2010.
English descriptors
- KwdEn :
- Acetylcysteine (analogs & derivatives), Acetylcysteine (toxicity), Animals, Behavior, Animal (physiology), Blotting, Western, Cell Count, Chromatography, High Pressure Liquid, Dopamine (physiology), Fluorescent Antibody Technique, Immunohistochemistry, Iron (metabolism), Male, Mice, Mice, Inbred C57BL, Microinjections, Microscopy, Electron, Nerve Degeneration (pathology), Neurons (metabolism), Neurons (pathology), Neuroprotective Agents (pharmacology), Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (pathology), Proteasome Endopeptidase Complex (metabolism), Proteasome Inhibitors, Substantia Nigra (metabolism), Substantia Nigra (pathology), Ubiquitin (metabolism).
- MESH :
- chemical , analogs & derivatives : Acetylcysteine.
- chemical , metabolism : Iron, Proteasome Endopeptidase Complex, Ubiquitin.
- chemical , pharmacology : Neuroprotective Agents.
- chemical , physiology : Dopamine.
- chemical , toxicity : Acetylcysteine.
- chemically induced : Parkinson Disease, Secondary.
- metabolism : Neurons, Substantia Nigra.
- pathology : Nerve Degeneration, Neurons, Parkinson Disease, Secondary, Substantia Nigra.
- physiology : Behavior, Animal.
- Animals, Blotting, Western, Cell Count, Chromatography, High Pressure Liquid, Fluorescent Antibody Technique, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Microinjections, Microscopy, Electron, Proteasome Inhibitors.
Abstract
Impairment of the ubiquitin proteasome system (UPS) has been proposed to play an important role in the pathogenesis of Parkinson's disease (PD). Mice with UPS impairment in the nigra have been used for investigating mechanisms underlying neurodegeneration and for testing pre-clinical drugs to treat PD. However, the pathological, biochemical and behavioral features of UPS impairment animal model of PD have not been fully evaluated. For this purpose, we developed a UPS impairment model of nigral dopamine (DA) neuron degeneration by microinjection with proteasome inhibitors lactacystin, PSI or MG-132 into the medial forebrain bundle (iMFB) of C57BL/6 mice and then systematically examined the animal's locomotor activities, and various pathological and biochemical markers of PD. We found that lactacystin iMFB induced a sustained DA neuron degeneration, which can be reproduced by PSI iMFB and MG-132 iMFB. In the animal model, DA neuron degenerated preferentially in the substantia nigra, accompanied by profound inhibition of proteasomal activity, activation of caspase 3, elevated insoluble ubiquitin conjugates and α-synuclein positive inclusion-like granules, activated glia, and decreased motor activities. Thus, this model recapitulates many neuropathological and behavioral features of PD, rendering it likely suitable for studying the mechanisms of nigral DA neuron degeneration and for testing the potential anti-PD medications.
DOI: 10.1111/j.1471-4159.2010.06914.x
PubMed: 20649845
Links to Exploration step
pubmed:20649845Le document en format XML
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last="Le">Weidong Le</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2010">2010</date><idno type="doi">10.1111/j.1471-4159.2010.06914.x</idno><idno type="RBID">pubmed:20649845</idno><idno type="pmid">20649845</idno><idno type="wicri:Area/PubMed/Corpus">000089</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease.</title><author><name sortKey="Xie, Wenjie" sort="Xie, Wenjie" uniqKey="Xie W" first="Wenjie" last="Xie">Wenjie Xie</name><affiliation><nlm:affiliation>Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Li, Xuping" sort="Li, Xuping" uniqKey="Li X" first="Xuping" last="Li">Xuping Li</name></author><author><name sortKey="Li, Chao" sort="Li, Chao" uniqKey="Li C" first="Chao" last="Li">Chao Li</name></author><author><name sortKey="Zhu, Wen" sort="Zhu, Wen" uniqKey="Zhu W" first="Wen" last="Zhu">Wen Zhu</name></author><author><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name></author><author><name sortKey="Le, Weidong" sort="Le, Weidong" uniqKey="Le W" first="Weidong" last="Le">Weidong Le</name></author></analytic><series><title level="j">Journal of neurochemistry</title><idno type="e-ISSN">1471-4159</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetylcysteine (analogs & derivatives)</term><term>Acetylcysteine (toxicity)</term><term>Animals</term><term>Behavior, Animal (physiology)</term><term>Blotting, Western</term><term>Cell Count</term><term>Chromatography, High Pressure Liquid</term><term>Dopamine (physiology)</term><term>Fluorescent Antibody Technique</term><term>Immunohistochemistry</term><term>Iron (metabolism)</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Microinjections</term><term>Microscopy, Electron</term><term>Nerve Degeneration (pathology)</term><term>Neurons (metabolism)</term><term>Neurons (pathology)</term><term>Neuroprotective Agents (pharmacology)</term><term>Parkinson Disease, Secondary (chemically induced)</term><term>Parkinson Disease, Secondary (pathology)</term><term>Proteasome Endopeptidase Complex (metabolism)</term><term>Proteasome Inhibitors</term><term>Substantia Nigra (metabolism)</term><term>Substantia Nigra (pathology)</term><term>Ubiquitin (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Acetylcysteine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Iron</term><term>Proteasome Endopeptidase Complex</term><term>Ubiquitin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Neuroprotective Agents</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Dopamine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Acetylcysteine</term></keywords><keywords scheme="MESH" qualifier="chemically induced" xml:lang="en"><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Neurons</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Nerve Degeneration</term><term>Neurons</term><term>Parkinson Disease, Secondary</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Behavior, Animal</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Blotting, Western</term><term>Cell Count</term><term>Chromatography, High Pressure Liquid</term><term>Fluorescent Antibody Technique</term><term>Immunohistochemistry</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Microinjections</term><term>Microscopy, Electron</term><term>Proteasome Inhibitors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Impairment of the ubiquitin proteasome system (UPS) has been proposed to play an important role in the pathogenesis of Parkinson's disease (PD). Mice with UPS impairment in the nigra have been used for investigating mechanisms underlying neurodegeneration and for testing pre-clinical drugs to treat PD. However, the pathological, biochemical and behavioral features of UPS impairment animal model of PD have not been fully evaluated. For this purpose, we developed a UPS impairment model of nigral dopamine (DA) neuron degeneration by microinjection with proteasome inhibitors lactacystin, PSI or MG-132 into the medial forebrain bundle (iMFB) of C57BL/6 mice and then systematically examined the animal's locomotor activities, and various pathological and biochemical markers of PD. We found that lactacystin iMFB induced a sustained DA neuron degeneration, which can be reproduced by PSI iMFB and MG-132 iMFB. In the animal model, DA neuron degenerated preferentially in the substantia nigra, accompanied by profound inhibition of proteasomal activity, activation of caspase 3, elevated insoluble ubiquitin conjugates and α-synuclein positive inclusion-like granules, activated glia, and decreased motor activities. Thus, this model recapitulates many neuropathological and behavioral features of PD, rendering it likely suitable for studying the mechanisms of nigral DA neuron degeneration and for testing the potential anti-PD medications.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">20649845</PMID><DateCreated><Year>2010</Year><Month>09</Month><Day>15</Day></DateCreated><DateCompleted><Year>2010</Year><Month>10</Month><Day>13</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1471-4159</ISSN><JournalIssue CitedMedium="Internet"><Volume>115</Volume><Issue>1</Issue><PubDate><Year>2010</Year><Month>Oct</Month></PubDate></JournalIssue><Title>Journal of neurochemistry</Title><ISOAbbreviation>J. Neurochem.</ISOAbbreviation></Journal><ArticleTitle>Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>188-99</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1111/j.1471-4159.2010.06914.x</ELocationID><Abstract><AbstractText>Impairment of the ubiquitin proteasome system (UPS) has been proposed to play an important role in the pathogenesis of Parkinson's disease (PD). Mice with UPS impairment in the nigra have been used for investigating mechanisms underlying neurodegeneration and for testing pre-clinical drugs to treat PD. However, the pathological, biochemical and behavioral features of UPS impairment animal model of PD have not been fully evaluated. For this purpose, we developed a UPS impairment model of nigral dopamine (DA) neuron degeneration by microinjection with proteasome inhibitors lactacystin, PSI or MG-132 into the medial forebrain bundle (iMFB) of C57BL/6 mice and then systematically examined the animal's locomotor activities, and various pathological and biochemical markers of PD. We found that lactacystin iMFB induced a sustained DA neuron degeneration, which can be reproduced by PSI iMFB and MG-132 iMFB. In the animal model, DA neuron degenerated preferentially in the substantia nigra, accompanied by profound inhibition of proteasomal activity, activation of caspase 3, elevated insoluble ubiquitin conjugates and α-synuclein positive inclusion-like granules, activated glia, and decreased motor activities. Thus, this model recapitulates many neuropathological and behavioral features of PD, rendering it likely suitable for studying the mechanisms of nigral DA neuron degeneration and for testing the potential anti-PD medications.</AbstractText><CopyrightInformation>© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Xie</LastName><ForeName>Wenjie</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Xuping</ForeName><Initials>X</Initials></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Chao</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Zhu</LastName><ForeName>Wen</ForeName><Initials>W</Initials></Author><Author ValidYN="Y"><LastName>Jankovic</LastName><ForeName>Joseph</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Le</LastName><ForeName>Weidong</ForeName><Initials>W</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2010</Year><Month>08</Month><Day>19</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Neurochem</MedlineTA><NlmUniqueID>2985190R</NlmUniqueID><ISSNLinking>0022-3042</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018696">Neuroprotective Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D061988">Proteasome Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D025801">Ubiquitin</NameOfSubstance></Chemical><Chemical><RegistryNumber>133343-34-7</RegistryNumber><NameOfSubstance UI="C067713">lactacystin</NameOfSubstance></Chemical><Chemical><RegistryNumber>E1UOL152H7</RegistryNumber><NameOfSubstance UI="D007501">Iron</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.25.1</RegistryNumber><NameOfSubstance UI="D046988">Proteasome Endopeptidase Complex</NameOfSubstance></Chemical><Chemical><RegistryNumber>VTD58H1Z2X</RegistryNumber><NameOfSubstance UI="D004298">Dopamine</NameOfSubstance></Chemical><Chemical><RegistryNumber>WYQ7N0BPYC</RegistryNumber><NameOfSubstance UI="D000111">Acetylcysteine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000111">Acetylcysteine</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000031">analogs & derivatives</QualifierName><QualifierName MajorTopicYN="N" UI="Q000633">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000818">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D001522">Behavior, Animal</DescriptorName><QualifierName MajorTopicYN="N" 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