Extracellular α-Synuclein Modulates Iron Metabolism Related Proteins via Endoplasmic Reticulum Stress in MES23.5 Dopaminergic Cells
Alpha-synuclein plays a vital role in the pathology of Parkinson’s disease (PD). Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic i...
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| Veröffentlicht in: | Neurochemical research 2021-06, Vol.46 (6), p.1502-1513 |
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| creator | Mi, Xiaoqing Li, Qijun Wen, Xiaoming Xie, Junxia Wang, Youcui Song, Ning |
| description | Alpha-synuclein plays a vital role in the pathology of Parkinson’s disease (PD). Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic intercellular transmitted α-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that α-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by α-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by α-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by α-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by α-synuclein. Taken together, these finding indicated that extracellular α-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted α-synuclein and iron metabolism disturbance in PD. |
| doi_str_mv | 10.1007/s11064-021-03292-3 |
| format | Article |
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Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic intercellular transmitted α-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that α-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by α-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by α-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by α-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by α-synuclein. Taken together, these finding indicated that extracellular α-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted α-synuclein and iron metabolism disturbance in PD.</description><identifier>ISSN: 0364-3190</identifier><identifier>EISSN: 1573-6903</identifier><identifier>DOI: 10.1007/s11064-021-03292-3</identifier><identifier>PMID: 33704649</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Autophagy ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cell Biology ; Divalent metal transporter-1 ; Dopamine receptors ; Endocytosis ; Endoplasmic reticulum ; Hepcidin ; Iron ; Iron regulatory protein ; Metabolism ; Movement disorders ; mRNA ; Neurochemistry ; Neurodegenerative diseases ; Neurology ; Neurosciences ; Original Paper ; Parkinson's disease ; Phagocytosis ; Phosphorylation ; Proteins ; Rapamycin ; Regulatory sequences ; Stress ; Synuclein ; Thapsigargin</subject><ispartof>Neurochemical research, 2021-06, Vol.46 (6), p.1502-1513</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-929220a9ff9fcc5bd0b31f1f1c964394cbd34c43d93614c60d97e192767544dc3</citedby><cites>FETCH-LOGICAL-c375t-929220a9ff9fcc5bd0b31f1f1c964394cbd34c43d93614c60d97e192767544dc3</cites><orcidid>0000-0002-4399-2236</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11064-021-03292-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11064-021-03292-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33704649$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mi, Xiaoqing</creatorcontrib><creatorcontrib>Li, Qijun</creatorcontrib><creatorcontrib>Wen, Xiaoming</creatorcontrib><creatorcontrib>Xie, Junxia</creatorcontrib><creatorcontrib>Wang, Youcui</creatorcontrib><creatorcontrib>Song, Ning</creatorcontrib><title>Extracellular α-Synuclein Modulates Iron Metabolism Related Proteins via Endoplasmic Reticulum Stress in MES23.5 Dopaminergic Cells</title><title>Neurochemical research</title><addtitle>Neurochem Res</addtitle><addtitle>Neurochem Res</addtitle><description>Alpha-synuclein plays a vital role in the pathology of Parkinson’s disease (PD). Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic intercellular transmitted α-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that α-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by α-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by α-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by α-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by α-synuclein. Taken together, these finding indicated that extracellular α-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted α-synuclein and iron metabolism disturbance in PD.</description><subject>Autophagy</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Biology</subject><subject>Divalent metal transporter-1</subject><subject>Dopamine receptors</subject><subject>Endocytosis</subject><subject>Endoplasmic reticulum</subject><subject>Hepcidin</subject><subject>Iron</subject><subject>Iron regulatory protein</subject><subject>Metabolism</subject><subject>Movement disorders</subject><subject>mRNA</subject><subject>Neurochemistry</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Original Paper</subject><subject>Parkinson's disease</subject><subject>Phagocytosis</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Regulatory sequences</subject><subject>Stress</subject><subject>Synuclein</subject><subject>Thapsigargin</subject><issn>0364-3190</issn><issn>1573-6903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kcFu1DAQhq0KRJfCC_SALHHhkjL2OIl8RNulrdQKxMLZcmynSpXEWztB9N4X6ovwTJ2wBSQOyAfLM9_8M-OfsWMBJwKgfp-FgEoVIEUBKLUs8ICtRFljUWnAZ2wFSGkUGg7Zy5xvAKhMihfsELEGVSm9YvebH1OyLvT93NvEfz4U27txdn3oRn4VPQWnkPlFivQMk21i3-WBfwlL3PPPKU5EZv69s3wz-rjrbR46R8DUubmfB76dUsiZL3KbrcSTkp_GnR26MaRrAtfUOb9iz1vb5_D66T5i3z5uvq7Pi8tPZxfrD5eFw7qcCk07SrC6bXXrXNl4aFC0dJyuFGrlGo_KKfQaK6FcBV7XQWhZV3WplHd4xN7tdXcp3s4hT2bo8rK7HUOcs5ElAHUqEQl9-w96E-c00nRECV3WUghJlNxTLsWcU2jNLnWDTXdGgFk8MnuPDH27-eWRWaTfPEnPzRD8n5LfphCAeyBTarwO6W_v_8g-AmEznPE</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Mi, Xiaoqing</creator><creator>Li, Qijun</creator><creator>Wen, Xiaoming</creator><creator>Xie, Junxia</creator><creator>Wang, Youcui</creator><creator>Song, Ning</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4399-2236</orcidid></search><sort><creationdate>20210601</creationdate><title>Extracellular α-Synuclein Modulates Iron Metabolism Related Proteins via Endoplasmic Reticulum Stress in MES23.5 Dopaminergic Cells</title><author>Mi, Xiaoqing ; 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Spreading of α-synuclein in neighboring cells was believed to contribute to progression in PD. How α-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant α-synuclein to mimic intercellular transmitted α-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that α-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by α-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by α-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by α-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by α-synuclein. Taken together, these finding indicated that extracellular α-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted α-synuclein and iron metabolism disturbance in PD.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>33704649</pmid><doi>10.1007/s11064-021-03292-3</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-4399-2236</orcidid></addata></record> |
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| subjects | Autophagy Biochemistry Biomedical and Life Sciences Biomedicine Cell Biology Divalent metal transporter-1 Dopamine receptors Endocytosis Endoplasmic reticulum Hepcidin Iron Iron regulatory protein Metabolism Movement disorders mRNA Neurochemistry Neurodegenerative diseases Neurology Neurosciences Original Paper Parkinson's disease Phagocytosis Phosphorylation Proteins Rapamycin Regulatory sequences Stress Synuclein Thapsigargin |
| title | Extracellular α-Synuclein Modulates Iron Metabolism Related Proteins via Endoplasmic Reticulum Stress in MES23.5 Dopaminergic Cells |
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