Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation
Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgeni...
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| Veröffentlicht in: | The Journal of clinical investigation 2009-11, Vol.119 (11), p.3257-3265 |
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| creator | Chen, Li Periquet, Magali Wang, Xu Negro, Alessandro McLean, Pamela J Hyman, Bradley T Feany, Mel B |
| description | Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation. |
| doi_str_mv | 10.1172/JCI39088 |
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Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI39088</identifier><identifier>PMID: 19855133</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Aging - physiology ; alpha-Synuclein - metabolism ; Analysis ; Animals ; Animals, Genetically Modified ; Disease Models, Animal ; Drosophila melanogaster ; Genetic aspects ; Humans ; Nerve proteins ; Neurons - metabolism ; Parkinson Disease - physiopathology ; Parkinson's disease ; Phosphorylation ; Physiological aspects ; Risk factors ; Serine ; Serine - metabolism ; Tyrosine ; Tyrosine - metabolism</subject><ispartof>The Journal of clinical investigation, 2009-11, Vol.119 (11), p.3257-3265</ispartof><rights>COPYRIGHT 2009 American Society for Clinical Investigation</rights><rights>Copyright © 2009, American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c613t-b44f9f3792192e9d872958e7a1a925ed712826f4ebdb482ddfae515c1fe0aa603</citedby><cites>FETCH-LOGICAL-c613t-b44f9f3792192e9d872958e7a1a925ed712826f4ebdb482ddfae515c1fe0aa603</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/PMC2769182/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769182/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,27925,27926,53792,53794</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19855133$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Li</creatorcontrib><creatorcontrib>Periquet, Magali</creatorcontrib><creatorcontrib>Wang, Xu</creatorcontrib><creatorcontrib>Negro, Alessandro</creatorcontrib><creatorcontrib>McLean, Pamela J</creatorcontrib><creatorcontrib>Hyman, Bradley T</creatorcontrib><creatorcontrib>Feany, Mel B</creatorcontrib><title>Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.</description><subject>Aging - physiology</subject><subject>alpha-Synuclein - metabolism</subject><subject>Analysis</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Disease Models, Animal</subject><subject>Drosophila melanogaster</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Nerve proteins</subject><subject>Neurons - metabolism</subject><subject>Parkinson Disease - physiopathology</subject><subject>Parkinson's disease</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Risk factors</subject><subject>Serine</subject><subject>Serine - metabolism</subject><subject>Tyrosine</subject><subject>Tyrosine - metabolism</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0l2L1DAUBuAgijuOgr9ACoLoRdcmbafJjbAMfowsLOjqbUjTkzaSJiVply34402dVbcwF1JCQ_Kc9-LkIPQcZ-cYV-Tt5_0hZxmlD9AGlyVNKcnpQ7TJMoJTVuX0DD0J4UeW4aIoi8foDDNaljjPN-jn9exd0BYSYZskgF-2Q-dCXH42YtTOJk4lwgydSMNsJ2lA26QTN5C4YVhq2wSUAjmGJFoLk3eju9VSj_Mx1JmpNlEb3boefKKc738HP0WPlDABnt39t-jbh_fX-0_p5dXHw_7iMpU7nI9pXRSKqbxiBDMCrKEVYSWFSmDBSAlNhQklO1VA3dQFJU2jBJS4lFhBJsQuy7fo3TF3mOoeGgl29MLwwete-Jk7ofn6xuqOt-6Gk2rHcGzmFr08BrTCANdWuchkr4PkFwQTUlWsWFR6QrVgIWY6C0rH45U_P-Hj10Cv5cmCN6uCaEa4HVsxhcAPX7_8v736vrav7tkOhBm75dWWNwpr-PoIZRya4EH97SHO-DKJ_M8kRvrifs__wbvRy38Bn4HZIQ</recordid><startdate>20091101</startdate><enddate>20091101</enddate><creator>Chen, Li</creator><creator>Periquet, Magali</creator><creator>Wang, Xu</creator><creator>Negro, Alessandro</creator><creator>McLean, Pamela J</creator><creator>Hyman, Bradley T</creator><creator>Feany, Mel B</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>5PM</scope></search><sort><creationdate>20091101</creationdate><title>Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation</title><author>Chen, Li ; Periquet, Magali ; Wang, Xu ; Negro, Alessandro ; McLean, Pamela J ; Hyman, Bradley T ; Feany, Mel B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c613t-b44f9f3792192e9d872958e7a1a925ed712826f4ebdb482ddfae515c1fe0aa603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Aging - physiology</topic><topic>alpha-Synuclein - metabolism</topic><topic>Analysis</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Disease Models, Animal</topic><topic>Drosophila melanogaster</topic><topic>Genetic aspects</topic><topic>Humans</topic><topic>Nerve proteins</topic><topic>Neurons - metabolism</topic><topic>Parkinson Disease - physiopathology</topic><topic>Parkinson's disease</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Risk factors</topic><topic>Serine</topic><topic>Serine - metabolism</topic><topic>Tyrosine</topic><topic>Tyrosine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Li</creatorcontrib><creatorcontrib>Periquet, Magali</creatorcontrib><creatorcontrib>Wang, Xu</creatorcontrib><creatorcontrib>Negro, Alessandro</creatorcontrib><creatorcontrib>McLean, Pamela J</creatorcontrib><creatorcontrib>Hyman, Bradley T</creatorcontrib><creatorcontrib>Feany, Mel B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Li</au><au>Periquet, Magali</au><au>Wang, Xu</au><au>Negro, Alessandro</au><au>McLean, Pamela J</au><au>Hyman, Bradley T</au><au>Feany, Mel B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2009-11-01</date><risdate>2009</risdate><volume>119</volume><issue>11</issue><spage>3257</spage><epage>3265</epage><pages>3257-3265</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wild-type human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>19855133</pmid><doi>10.1172/JCI39088</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aging - physiology alpha-Synuclein - metabolism Analysis Animals Animals, Genetically Modified Disease Models, Animal Drosophila melanogaster Genetic aspects Humans Nerve proteins Neurons - metabolism Parkinson Disease - physiopathology Parkinson's disease Phosphorylation Physiological aspects Risk factors Serine Serine - metabolism Tyrosine Tyrosine - metabolism |
| title | Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation |
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