Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease.
Identifieur interne : 000505 ( Main/Exploration ); précédent : 000504; suivant : 000506Proteasome inhibition modeling nigral neuron degeneration in Parkinson's disease.
Auteurs : Wenjie Xie [États-Unis] ; Xuping Li ; Chao Li ; Wen Zhu ; Joseph Jankovic [États-Unis] ; 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
Affiliations:
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sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name><affiliation><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university" n="3">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Le, Weidong" sort="Le, Weidong" uniqKey="Le W" first="Weidong" 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><idno type="wicri:Area/PubMed/Curation">000089</idno><idno type="wicri:Area/PubMed/Checkpoint">000088</idno><idno type="wicri:Area/Ncbi/Merge">000294</idno><idno type="wicri:Area/Ncbi/Curation">000294</idno><idno 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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><affiliation><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university" n="3">Baylor College of Medicine</orgName></affiliation></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><affiliations><list><country><li>États-Unis</li></country><region><li>Texas</li></region><settlement><li>Houston</li></settlement><orgName><li>Baylor College of Medicine</li></orgName></list><tree><noCountry><name sortKey="Le, Weidong" sort="Le, Weidong" uniqKey="Le W" first="Weidong" last="Le">Weidong Le</name><name sortKey="Li, Chao" sort="Li, Chao" uniqKey="Li C" first="Chao" last="Li">Chao Li</name><name sortKey="Li, Xuping" sort="Li, Xuping" uniqKey="Li X" first="Xuping" last="Li">Xuping Li</name><name sortKey="Zhu, Wen" sort="Zhu, Wen" uniqKey="Zhu W" first="Wen" last="Zhu">Wen Zhu</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Xie, Wenjie" sort="Xie, Wenjie" uniqKey="Xie W" first="Wenjie" last="Xie">Wenjie Xie</name></noRegion><name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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