Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration
The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher pla...
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creator | Frank-Cannon, Tamy C Tran, Thi Ruhn, Kelly A Martinez, Terina N Hong, John Marvin, Marian Hartley, Meagan Trevino, Isaac O'Brien, Daniel E Casey, Bradford Goldberg, Matthew S Tansey, Malu G |
description | The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin-/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway. |
doi_str_mv | 10.1523/JNEUROSCI.3001-08.2008 |
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Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin-/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.3001-08.2008</identifier><identifier>PMID: 18945890</identifier><language>eng</language><publisher>United States: Soc Neuroscience</publisher><subject>Animals ; Behavior, Animal - drug effects ; Cell Survival - drug effects ; Cytokines - metabolism ; Dopamine - metabolism ; Exploratory Behavior - drug effects ; Exploratory Behavior - physiology ; Gait Disorders, Neurologic - etiology ; Gait Disorders, Neurologic - genetics ; Heme Oxygenase-1 - genetics ; Heme Oxygenase-1 - metabolism ; Inflammation - chemically induced ; Inflammation - complications ; Mice ; Mice, Knockout ; Motor Activity - drug effects ; Motor Activity - genetics ; Multivariate Analysis ; Nerve Degeneration - etiology ; Nerve Degeneration - metabolism ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; Nitric Oxide Synthase Type II - genetics ; Nitric Oxide Synthase Type II - metabolism ; Polysaccharides ; Psychomotor Performance - drug effects ; Psychomotor Performance - physiology ; Rotarod Performance Test ; Substantia Nigra - metabolism ; Substantia Nigra - pathology ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Tyrosine 3-Monooxygenase ; Ubiquitin-Protein Ligases - deficiency</subject><ispartof>The Journal of neuroscience, 2008-10, Vol.28 (43), p.10825-10834</ispartof><rights>Copyright © 2008 Society for Neuroscience 0270-6474/08/2810825-10$15.00/0 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-9926dedab74814e4875531eb1162133182296e2d7801305face07263f9d39f8c3</citedby><cites>FETCH-LOGICAL-c511t-9926dedab74814e4875531eb1162133182296e2d7801305face07263f9d39f8c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603252/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603252/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18945890$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Frank-Cannon, Tamy C</creatorcontrib><creatorcontrib>Tran, Thi</creatorcontrib><creatorcontrib>Ruhn, Kelly A</creatorcontrib><creatorcontrib>Martinez, Terina N</creatorcontrib><creatorcontrib>Hong, John</creatorcontrib><creatorcontrib>Marvin, Marian</creatorcontrib><creatorcontrib>Hartley, Meagan</creatorcontrib><creatorcontrib>Trevino, Isaac</creatorcontrib><creatorcontrib>O'Brien, Daniel E</creatorcontrib><creatorcontrib>Casey, Bradford</creatorcontrib><creatorcontrib>Goldberg, Matthew S</creatorcontrib><creatorcontrib>Tansey, Malu G</creatorcontrib><title>Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin-/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.</description><subject>Animals</subject><subject>Behavior, Animal - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cytokines - metabolism</subject><subject>Dopamine - metabolism</subject><subject>Exploratory Behavior - drug effects</subject><subject>Exploratory Behavior - physiology</subject><subject>Gait Disorders, Neurologic - etiology</subject><subject>Gait Disorders, Neurologic - genetics</subject><subject>Heme Oxygenase-1 - genetics</subject><subject>Heme Oxygenase-1 - metabolism</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - complications</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Motor Activity - drug effects</subject><subject>Motor Activity - genetics</subject><subject>Multivariate Analysis</subject><subject>Nerve Degeneration - etiology</subject><subject>Nerve Degeneration - metabolism</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nitric Oxide Synthase Type II - genetics</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Polysaccharides</subject><subject>Psychomotor Performance - drug effects</subject><subject>Psychomotor Performance - physiology</subject><subject>Rotarod Performance Test</subject><subject>Substantia Nigra - metabolism</subject><subject>Substantia Nigra - pathology</subject><subject>Superoxide Dismutase - genetics</subject><subject>Superoxide Dismutase - metabolism</subject><subject>Tyrosine 3-Monooxygenase</subject><subject>Ubiquitin-Protein Ligases - deficiency</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU9vEzEQxS0EoiHwFao9IS4bZuz9Y1-QUCgQVLWoEK6W451NDN7d1t4Q5dvjVaICpzm8N2-e5sfYJcICSy7efrm5Wt_dfluuFgIAc5ALDiCfsFlSVc4LwKdsBryGvCrq4oK9iPEnANSA9XN2gVIVpVQwY-uvJvxyffaBWmcd9faYrXobyESK2Y-97ymYjfNuPGbjkKTWm64zoxv6_I68GanJbtw2GJ8StjS5J-0le9YaH-nVec7Z-uPV9-Xn_Pr202r5_jq3JeKYK8WrhhqzqQuJBRWyLkuBtEGsOAqBknNVEW9qCSigbI0lqHklWtUI1Uor5uzdKfd-v-mosdSPqYq-D64z4agH4_T_Su92ejv81rwCwdMf5-z1OSAMD3uKo-5ctOS96WnYR12p9DGZusxZdTLaMMQYqH08gqAnIvqRiJ6IaJB6IpIWL_-t-HftjCAZ3pwMO7fdHVwgHTvjfbKjPhwOXOpCpCOSl-IPQrCXAg</recordid><startdate>20081022</startdate><enddate>20081022</enddate><creator>Frank-Cannon, Tamy C</creator><creator>Tran, Thi</creator><creator>Ruhn, Kelly A</creator><creator>Martinez, Terina N</creator><creator>Hong, John</creator><creator>Marvin, Marian</creator><creator>Hartley, Meagan</creator><creator>Trevino, Isaac</creator><creator>O'Brien, Daniel E</creator><creator>Casey, Bradford</creator><creator>Goldberg, Matthew S</creator><creator>Tansey, Malu G</creator><general>Soc Neuroscience</general><general>Society for Neuroscience</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081022</creationdate><title>Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration</title><author>Frank-Cannon, Tamy C ; Tran, Thi ; Ruhn, Kelly A ; Martinez, Terina N ; Hong, John ; Marvin, Marian ; Hartley, Meagan ; Trevino, Isaac ; O'Brien, Daniel E ; Casey, Bradford ; Goldberg, Matthew S ; Tansey, Malu G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-9926dedab74814e4875531eb1162133182296e2d7801305face07263f9d39f8c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Behavior, Animal - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Cytokines - metabolism</topic><topic>Dopamine - metabolism</topic><topic>Exploratory Behavior - drug effects</topic><topic>Exploratory Behavior - physiology</topic><topic>Gait Disorders, Neurologic - etiology</topic><topic>Gait Disorders, Neurologic - genetics</topic><topic>Heme Oxygenase-1 - genetics</topic><topic>Heme Oxygenase-1 - metabolism</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - complications</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Motor Activity - drug effects</topic><topic>Motor Activity - genetics</topic><topic>Multivariate Analysis</topic><topic>Nerve Degeneration - etiology</topic><topic>Nerve Degeneration - metabolism</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Nitric Oxide Synthase Type II - genetics</topic><topic>Nitric Oxide Synthase Type II - metabolism</topic><topic>Polysaccharides</topic><topic>Psychomotor Performance - drug effects</topic><topic>Psychomotor Performance - physiology</topic><topic>Rotarod Performance Test</topic><topic>Substantia Nigra - metabolism</topic><topic>Substantia Nigra - pathology</topic><topic>Superoxide Dismutase - genetics</topic><topic>Superoxide Dismutase - metabolism</topic><topic>Tyrosine 3-Monooxygenase</topic><topic>Ubiquitin-Protein Ligases - deficiency</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Frank-Cannon, Tamy C</creatorcontrib><creatorcontrib>Tran, Thi</creatorcontrib><creatorcontrib>Ruhn, Kelly A</creatorcontrib><creatorcontrib>Martinez, Terina N</creatorcontrib><creatorcontrib>Hong, John</creatorcontrib><creatorcontrib>Marvin, Marian</creatorcontrib><creatorcontrib>Hartley, Meagan</creatorcontrib><creatorcontrib>Trevino, Isaac</creatorcontrib><creatorcontrib>O'Brien, Daniel E</creatorcontrib><creatorcontrib>Casey, Bradford</creatorcontrib><creatorcontrib>Goldberg, Matthew S</creatorcontrib><creatorcontrib>Tansey, Malu G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Frank-Cannon, Tamy C</au><au>Tran, Thi</au><au>Ruhn, Kelly A</au><au>Martinez, Terina N</au><au>Hong, John</au><au>Marvin, Marian</au><au>Hartley, Meagan</au><au>Trevino, Isaac</au><au>O'Brien, Daniel E</au><au>Casey, Bradford</au><au>Goldberg, Matthew S</au><au>Tansey, Malu G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2008-10-22</date><risdate>2008</risdate><volume>28</volume><issue>43</issue><spage>10825</spage><epage>10834</epage><pages>10825-10834</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin-/-) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin-/- mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin-/- mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin-/- mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.</abstract><cop>United States</cop><pub>Soc Neuroscience</pub><pmid>18945890</pmid><doi>10.1523/JNEUROSCI.3001-08.2008</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Behavior, Animal - drug effects Cell Survival - drug effects Cytokines - metabolism Dopamine - metabolism Exploratory Behavior - drug effects Exploratory Behavior - physiology Gait Disorders, Neurologic - etiology Gait Disorders, Neurologic - genetics Heme Oxygenase-1 - genetics Heme Oxygenase-1 - metabolism Inflammation - chemically induced Inflammation - complications Mice Mice, Knockout Motor Activity - drug effects Motor Activity - genetics Multivariate Analysis Nerve Degeneration - etiology Nerve Degeneration - metabolism NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Nitric Oxide Synthase Type II - genetics Nitric Oxide Synthase Type II - metabolism Polysaccharides Psychomotor Performance - drug effects Psychomotor Performance - physiology Rotarod Performance Test Substantia Nigra - metabolism Substantia Nigra - pathology Superoxide Dismutase - genetics Superoxide Dismutase - metabolism Tyrosine 3-Monooxygenase Ubiquitin-Protein Ligases - deficiency |
title | Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration |
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