A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons
Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction...
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| Veröffentlicht in: | Human molecular genetics 2014-12, Vol.23 (24), p.6567-6574 |
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| creator | Luo, Jing Sun, Lixin Lin, Xian Liu, Guoxiang Yu, Jia Parisiadou, Loukia Xie, Chengsong Ding, Jinhui Cai, Huaibin |
| description | Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of α-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human α-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. α-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T α-syn. Furthermore, overexpression of α-syn A53T mutation significantly increased the CN-dependent nuclear import of NFATc3 in the mDA neurons of transgenic mice. More importantly, a pharmacological inhibition of CN by cyclosporine A (CsA) ameliorated the α-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in α-syn-mediated degeneration of mDA neurons in PD. |
| doi_str_mv | 10.1093/hmg/ddu377 |
| format | Article |
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Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of α-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human α-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. α-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T α-syn. Furthermore, overexpression of α-syn A53T mutation significantly increased the CN-dependent nuclear import of NFATc3 in the mDA neurons of transgenic mice. More importantly, a pharmacological inhibition of CN by cyclosporine A (CsA) ameliorated the α-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in α-syn-mediated degeneration of mDA neurons in PD.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddu377</identifier><identifier>PMID: 25051958</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; Animals ; Apoptosis - drug effects ; Calcineurin - genetics ; Calcineurin - metabolism ; Calcineurin Inhibitors - pharmacology ; Cyclosporine - pharmacology ; Dopaminergic Neurons - drug effects ; Dopaminergic Neurons - metabolism ; Dopaminergic Neurons - pathology ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Mesencephalon - drug effects ; Mesencephalon - metabolism ; Mesencephalon - pathology ; Mice ; Mice, Transgenic ; Mutation ; NFATC Transcription Factors - genetics ; NFATC Transcription Factors - metabolism ; Parkinson Disease - drug therapy ; Parkinson Disease - genetics ; Parkinson Disease - metabolism ; Parkinson Disease - pathology ; Primary Cell Culture ; Signal Transduction</subject><ispartof>Human molecular genetics, 2014-12, Vol.23 (24), p.6567-6574</ispartof><rights>Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.</rights><rights>Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25051958$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luo, Jing</creatorcontrib><creatorcontrib>Sun, Lixin</creatorcontrib><creatorcontrib>Lin, Xian</creatorcontrib><creatorcontrib>Liu, Guoxiang</creatorcontrib><creatorcontrib>Yu, Jia</creatorcontrib><creatorcontrib>Parisiadou, Loukia</creatorcontrib><creatorcontrib>Xie, Chengsong</creatorcontrib><creatorcontrib>Ding, Jinhui</creatorcontrib><creatorcontrib>Cai, Huaibin</creatorcontrib><title>A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of α-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human α-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. α-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T α-syn. Furthermore, overexpression of α-syn A53T mutation significantly increased the CN-dependent nuclear import of NFATc3 in the mDA neurons of transgenic mice. More importantly, a pharmacological inhibition of CN by cyclosporine A (CsA) ameliorated the α-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in α-syn-mediated degeneration of mDA neurons in PD.</description><subject>alpha-Synuclein - genetics</subject><subject>alpha-Synuclein - metabolism</subject><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Calcineurin - genetics</subject><subject>Calcineurin - metabolism</subject><subject>Calcineurin Inhibitors - pharmacology</subject><subject>Cyclosporine - pharmacology</subject><subject>Dopaminergic Neurons - drug effects</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Dopaminergic Neurons - pathology</subject><subject>Gene Expression Regulation</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mesencephalon - drug effects</subject><subject>Mesencephalon - metabolism</subject><subject>Mesencephalon - pathology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>NFATC Transcription Factors - genetics</subject><subject>NFATC Transcription Factors - metabolism</subject><subject>Parkinson Disease - drug therapy</subject><subject>Parkinson Disease - genetics</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson Disease - pathology</subject><subject>Primary Cell Culture</subject><subject>Signal Transduction</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1P3DAQtapWZYFe-gMqH3sJ-DNOLkgrVNpKCC70HE3sya6rxA5xstWKX8Uf6W_CCFrBidOM5s2892aGkM-cnXBWy9PtsDl1bpHGvCMrrkpWCFbJ92TF6lIVZc3KA3KY0m_GeKmk-UgOhGaa17pakbs1tdBbH3CZfCgoBEevLtY3hcMRg8Mw0xHm7R_YU5-oD7vY79DlhP69L9I-LLbHPOeDW2yuO9xgwAlmHwONHR28ayfI3S6OMGSVaeMtfRSLIR2TDx30CT89xyPy6-LbzfmP4vL6-8_z9WUxirqei9aUurLWSN1Z05VWGQ2iBY5gUUvBQQmnW9RCo6yqfBFlEFhnLEBG21oekbMn3nFpB3Q2LzVB34yTH2DaNxF88xoJftts4q5RQjHBdCb4-kwwxdsF09wMPlnsewgYl9Rww7iqDK_l262lMMwIIR5tfXlp67-ff8-RD7velMc</recordid><startdate>20141215</startdate><enddate>20141215</enddate><creator>Luo, Jing</creator><creator>Sun, Lixin</creator><creator>Lin, Xian</creator><creator>Liu, Guoxiang</creator><creator>Yu, Jia</creator><creator>Parisiadou, Loukia</creator><creator>Xie, Chengsong</creator><creator>Ding, Jinhui</creator><creator>Cai, Huaibin</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20141215</creationdate><title>A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons</title><author>Luo, Jing ; Sun, Lixin ; Lin, Xian ; Liu, Guoxiang ; Yu, Jia ; Parisiadou, Loukia ; Xie, Chengsong ; Ding, Jinhui ; Cai, Huaibin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p299t-b7658cc735fc7f6c475a2ba1eace5321a42d5be525e38810947ea0f7caa321b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>alpha-Synuclein - genetics</topic><topic>alpha-Synuclein - metabolism</topic><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Calcineurin - genetics</topic><topic>Calcineurin - metabolism</topic><topic>Calcineurin Inhibitors - pharmacology</topic><topic>Cyclosporine - pharmacology</topic><topic>Dopaminergic Neurons - drug effects</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Dopaminergic Neurons - pathology</topic><topic>Gene Expression Regulation</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mesencephalon - drug effects</topic><topic>Mesencephalon - metabolism</topic><topic>Mesencephalon - pathology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>NFATC Transcription Factors - genetics</topic><topic>NFATC Transcription Factors - metabolism</topic><topic>Parkinson Disease - drug therapy</topic><topic>Parkinson Disease - genetics</topic><topic>Parkinson Disease - metabolism</topic><topic>Parkinson Disease - pathology</topic><topic>Primary Cell Culture</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Luo, Jing</creatorcontrib><creatorcontrib>Sun, Lixin</creatorcontrib><creatorcontrib>Lin, Xian</creatorcontrib><creatorcontrib>Liu, Guoxiang</creatorcontrib><creatorcontrib>Yu, Jia</creatorcontrib><creatorcontrib>Parisiadou, Loukia</creatorcontrib><creatorcontrib>Xie, Chengsong</creatorcontrib><creatorcontrib>Ding, Jinhui</creatorcontrib><creatorcontrib>Cai, Huaibin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Luo, Jing</au><au>Sun, Lixin</au><au>Lin, Xian</au><au>Liu, Guoxiang</au><au>Yu, Jia</au><au>Parisiadou, Loukia</au><au>Xie, Chengsong</au><au>Ding, Jinhui</au><au>Cai, Huaibin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2014-12-15</date><risdate>2014</risdate><volume>23</volume><issue>24</issue><spage>6567</spage><epage>6574</epage><pages>6567-6574</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Parkinson's disease (PD), the most common degenerative movement disorder, is caused by a preferential loss of midbrain dopaminergic (mDA) neurons. Both α-synuclein (α-syn) missense and multiplication mutations have been linked to PD. However, the underlying intracellular signalling transduction pathways of α-syn-mediated mDA neurodegeneration remain elusive. Here, we show that transgenic expression of PD-related human α-syn A53T missense mutation promoted calcineurin (CN) activity and the subsequent nuclear translocation of nuclear factor of activated T cells (NFATs) in mDA neurons. α-syn enhanced the phosphatase activity of CN in both cell-free assays and cell lines transfected with either human wild-type or A53T α-syn. Furthermore, overexpression of α-syn A53T mutation significantly increased the CN-dependent nuclear import of NFATc3 in the mDA neurons of transgenic mice. More importantly, a pharmacological inhibition of CN by cyclosporine A (CsA) ameliorated the α-syn-induced loss of mDA neurons. These findings demonstrate an active involvement of CN- and NFAT-mediated signalling pathway in α-syn-mediated degeneration of mDA neurons in PD.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>25051958</pmid><doi>10.1093/hmg/ddu377</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | alpha-Synuclein - genetics alpha-Synuclein - metabolism Animals Apoptosis - drug effects Calcineurin - genetics Calcineurin - metabolism Calcineurin Inhibitors - pharmacology Cyclosporine - pharmacology Dopaminergic Neurons - drug effects Dopaminergic Neurons - metabolism Dopaminergic Neurons - pathology Gene Expression Regulation HEK293 Cells Humans Mesencephalon - drug effects Mesencephalon - metabolism Mesencephalon - pathology Mice Mice, Transgenic Mutation NFATC Transcription Factors - genetics NFATC Transcription Factors - metabolism Parkinson Disease - drug therapy Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson Disease - pathology Primary Cell Culture Signal Transduction |
| title | A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons |
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