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Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats
The pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated alpha-synuclein are demonstrat...
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| Published in: | PloS one 2010-04, Vol.5 (4), p.e9956 |
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| creator | Yu, Zhongwang Xu, Xiaohui Xiang, Zhenghua Zhou, Jianfeng Zhang, Zhaohuan Hu, Chun He, Cheng |
| description | The pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated alpha-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of alpha-synuclein is relevant to the pathogenesis of PD is unknown.
In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects.
Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD. |
| doi_str_mv | 10.1371/journal.pone.0009956 |
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In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects.
Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0009956</identifier><identifier>PMID: 20386702</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>alpha-Synuclein - pharmacology ; alpha-Synuclein - toxicity ; Animals ; Apoptosis ; Axons ; Biochemistry/Chemical Biology of the Cell ; Biochemistry/Macromolecular Chemistry ; Biocompatibility ; Cell Biology/Cellular Death and Stress Responses ; Cell death ; Cell Death - drug effects ; Cells, Cultured ; Degeneration ; Dopamine ; Dopamine D2 receptors ; Down-Regulation - genetics ; Etiology ; Gait Disorders, Neurologic - chemically induced ; Inclusions ; Kinases ; Lewy bodies ; Locomotion ; Movement disorders ; Neostriatum ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Neurons - pathology ; Neuroscience/Neurobiology of Disease and Regeneration ; Neurosciences ; Nitrates - pharmacology ; Nitrates - toxicity ; Nitration ; Parkinson Disease - etiology ; Parkinson's disease ; Pathogenesis ; Rats ; Receptors, Dopamine D2 - genetics ; Rodents ; Substantia nigra ; Substantia Nigra - pathology ; Synuclein</subject><ispartof>PloS one, 2010-04, Vol.5 (4), p.e9956</ispartof><rights>2010 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Yu et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-2add323624ae6e54f50e01a1c44bb6257af76f08071aa40b8cb3e3e4d642a0693</citedby><cites>FETCH-LOGICAL-c525t-2add323624ae6e54f50e01a1c44bb6257af76f08071aa40b8cb3e3e4d642a0693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1289442158/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1289442158?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20386702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cookson, Mark R.</contributor><creatorcontrib>Yu, Zhongwang</creatorcontrib><creatorcontrib>Xu, Xiaohui</creatorcontrib><creatorcontrib>Xiang, Zhenghua</creatorcontrib><creatorcontrib>Zhou, Jianfeng</creatorcontrib><creatorcontrib>Zhang, Zhaohuan</creatorcontrib><creatorcontrib>Hu, Chun</creatorcontrib><creatorcontrib>He, Cheng</creatorcontrib><title>Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated alpha-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of alpha-synuclein is relevant to the pathogenesis of PD is unknown.
In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects.
Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.</description><subject>alpha-Synuclein - pharmacology</subject><subject>alpha-Synuclein - toxicity</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Axons</subject><subject>Biochemistry/Chemical Biology of the Cell</subject><subject>Biochemistry/Macromolecular Chemistry</subject><subject>Biocompatibility</subject><subject>Cell Biology/Cellular Death and Stress Responses</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cells, Cultured</subject><subject>Degeneration</subject><subject>Dopamine</subject><subject>Dopamine D2 receptors</subject><subject>Down-Regulation - genetics</subject><subject>Etiology</subject><subject>Gait Disorders, Neurologic - chemically induced</subject><subject>Inclusions</subject><subject>Kinases</subject><subject>Lewy bodies</subject><subject>Locomotion</subject><subject>Movement disorders</subject><subject>Neostriatum</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurons</subject><subject>Neurons - pathology</subject><subject>Neuroscience/Neurobiology of Disease and Regeneration</subject><subject>Neurosciences</subject><subject>Nitrates - pharmacology</subject><subject>Nitrates - toxicity</subject><subject>Nitration</subject><subject>Parkinson Disease - etiology</subject><subject>Parkinson's disease</subject><subject>Pathogenesis</subject><subject>Rats</subject><subject>Receptors, Dopamine D2 - genetics</subject><subject>Rodents</subject><subject>Substantia nigra</subject><subject>Substantia Nigra - pathology</subject><subject>Synuclein</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uk1v1DAQjRCIlsI_QBCJc5bxZ5ILEqpoqVTBBc7WOJnsepW1g50g9d_j7aZVe-Bka_zem-eZVxTvGWyYqNnnfViix3EzBU8bAGhbpV8U56wVvNIcxMsn97PiTUp7ACUarV8XZ7nU6Br4eYE_3Bxxpr7Ecdphle780o3kfOl8v3SUynlH5RhSKsNQ9mHCg_MUt64rPS0x-JSB95i02DSjnx2W3m0jHvFZOb0tXg04Jnq3nhfF76tvvy6_V7c_r28uv95WneJqrjj2veBCc4mkSclBAQFD1klpreaqxqHWAzRQM0QJtumsIEGy15Ij6FZcFB9PulN2a9bpJMN400rJmWoy4uaE6APuzRTdAeOdCejMfSHErcE4u_x9YxtA4DKPSVjZKoYD8IaIwBIb6rrPWl_Wbos9UN-Rz2Mcn4k-f_FuZ7bhr-GNYloezXxaBWL4s1Ca_2NZnlBdzCuINDx2YGCOMXhgmWMMzBqDTPvw1N0j6WHv4h8bELIz</recordid><startdate>20100408</startdate><enddate>20100408</enddate><creator>Yu, Zhongwang</creator><creator>Xu, Xiaohui</creator><creator>Xiang, Zhenghua</creator><creator>Zhou, Jianfeng</creator><creator>Zhang, Zhaohuan</creator><creator>Hu, Chun</creator><creator>He, Cheng</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20100408</creationdate><title>Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats</title><author>Yu, Zhongwang ; Xu, Xiaohui ; Xiang, Zhenghua ; Zhou, Jianfeng ; Zhang, Zhaohuan ; Hu, Chun ; He, Cheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c525t-2add323624ae6e54f50e01a1c44bb6257af76f08071aa40b8cb3e3e4d642a0693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>alpha-Synuclein - pharmacology</topic><topic>alpha-Synuclein - toxicity</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Axons</topic><topic>Biochemistry/Chemical Biology of the Cell</topic><topic>Biochemistry/Macromolecular Chemistry</topic><topic>Biocompatibility</topic><topic>Cell Biology/Cellular Death and Stress Responses</topic><topic>Cell death</topic><topic>Cell Death - drug effects</topic><topic>Cells, Cultured</topic><topic>Degeneration</topic><topic>Dopamine</topic><topic>Dopamine D2 receptors</topic><topic>Down-Regulation - genetics</topic><topic>Etiology</topic><topic>Gait Disorders, Neurologic - chemically induced</topic><topic>Inclusions</topic><topic>Kinases</topic><topic>Lewy bodies</topic><topic>Locomotion</topic><topic>Movement disorders</topic><topic>Neostriatum</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neurons</topic><topic>Neurons - pathology</topic><topic>Neuroscience/Neurobiology of Disease and Regeneration</topic><topic>Neurosciences</topic><topic>Nitrates - 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Accumulations of nitrated alpha-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of alpha-synuclein is relevant to the pathogenesis of PD is unknown.
In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects.
Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20386702</pmid><doi>10.1371/journal.pone.0009956</doi><oa>free_for_read</oa></addata></record> |
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| subjects | alpha-Synuclein - pharmacology alpha-Synuclein - toxicity Animals Apoptosis Axons Biochemistry/Chemical Biology of the Cell Biochemistry/Macromolecular Chemistry Biocompatibility Cell Biology/Cellular Death and Stress Responses Cell death Cell Death - drug effects Cells, Cultured Degeneration Dopamine Dopamine D2 receptors Down-Regulation - genetics Etiology Gait Disorders, Neurologic - chemically induced Inclusions Kinases Lewy bodies Locomotion Movement disorders Neostriatum Neurodegeneration Neurodegenerative diseases Neurons Neurons - pathology Neuroscience/Neurobiology of Disease and Regeneration Neurosciences Nitrates - pharmacology Nitrates - toxicity Nitration Parkinson Disease - etiology Parkinson's disease Pathogenesis Rats Receptors, Dopamine D2 - genetics Rodents Substantia nigra Substantia Nigra - pathology Synuclein |
| title | Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats |
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