Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo
An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related syn...
Gespeichert in:
Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (41), p.E3945-E3945 |
---|---|
Hauptverfasser: | , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | E3945 |
---|---|
container_issue | 41 |
container_start_page | E3945 |
container_title | Proceedings of the National Academy of Sciences - PNAS |
container_volume | 110 |
creator | Oueslati, Abid Schneider, Bernard L Aebischer, Patrick Lashuel, Hilal A |
description | An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/ α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. [PUBLICATION ABSTRACT] |
doi_str_mv | 10.1073/pnas.1309991110 |
format | Article |
fullrecord | <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_miscellaneous_1512331841</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1512331841</sourcerecordid><originalsourceid>FETCH-LOGICAL-p131t-10eec8c4aeb82e60b37c892fd8aec99aa98c67955739a9343b82416c029f2aff3</originalsourceid><addsrcrecordid>eNpdzr1PwzAQBXALgUQpzKyWWFhSfLaT2BNCFV9SJRhgrlz3UtyaOMR2Rf97LMHEcm_5vacj5BLYDFgrbobexBkIprUGAHZEJsA0VI3U7JhMGONtpSSXp-Qsxi1jTNeKTcjuNfhQebdDunNlASmnI26yNwkjjejRJrdHanIKw4fZOEtvq3jos_XoelquGU1vC-jXNOZhGDHG0nQp0hS-nXXpQAvcu304Jyed8REv_nJK3h_u3-ZP1eLl8Xl-t6gGEJAqYIhWWWlwpTg2bCVaqzTv1sqg1doYrWzT6rpuhTZaSFGYhMYyrjtuuk5MyfXv7jCGr4wxLT9dtOi96THkuIQauBCgJBR69Y9uQx778t0SpOR1MdCKH_jKahA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1442584117</pqid></control><display><type>article</type><title>Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo</title><source>JSTOR Archive Collection A-Z Listing</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Oueslati, Abid ; Schneider, Bernard L ; Aebischer, Patrick ; Lashuel, Hilal A</creator><creatorcontrib>Oueslati, Abid ; Schneider, Bernard L ; Aebischer, Patrick ; Lashuel, Hilal A</creatorcontrib><description>An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/ α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. [PUBLICATION ABSTRACT]</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1309991110</identifier><language>eng</language><publisher>Washington: National Academy of Sciences</publisher><subject>Kinases ; Parkinson's disease ; Phosphorylation ; Poliomyelitis ; Proteins ; Rodents ; Toxicity</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-10, Vol.110 (41), p.E3945-E3945</ispartof><rights>Copyright National Academy of Sciences Oct 8, 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids></links><search><creatorcontrib>Oueslati, Abid</creatorcontrib><creatorcontrib>Schneider, Bernard L</creatorcontrib><creatorcontrib>Aebischer, Patrick</creatorcontrib><creatorcontrib>Lashuel, Hilal A</creatorcontrib><title>Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo</title><title>Proceedings of the National Academy of Sciences - PNAS</title><description>An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/ α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. [PUBLICATION ABSTRACT]</description><subject>Kinases</subject><subject>Parkinson's disease</subject><subject>Phosphorylation</subject><subject>Poliomyelitis</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Toxicity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNpdzr1PwzAQBXALgUQpzKyWWFhSfLaT2BNCFV9SJRhgrlz3UtyaOMR2Rf97LMHEcm_5vacj5BLYDFgrbobexBkIprUGAHZEJsA0VI3U7JhMGONtpSSXp-Qsxi1jTNeKTcjuNfhQebdDunNlASmnI26yNwkjjejRJrdHanIKw4fZOEtvq3jos_XoelquGU1vC-jXNOZhGDHG0nQp0hS-nXXpQAvcu304Jyed8REv_nJK3h_u3-ZP1eLl8Xl-t6gGEJAqYIhWWWlwpTg2bCVaqzTv1sqg1doYrWzT6rpuhTZaSFGYhMYyrjtuuk5MyfXv7jCGr4wxLT9dtOi96THkuIQauBCgJBR69Y9uQx778t0SpOR1MdCKH_jKahA</recordid><startdate>20131008</startdate><enddate>20131008</enddate><creator>Oueslati, Abid</creator><creator>Schneider, Bernard L</creator><creator>Aebischer, Patrick</creator><creator>Lashuel, Hilal A</creator><general>National Academy of Sciences</general><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7U7</scope></search><sort><creationdate>20131008</creationdate><title>Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo</title><author>Oueslati, Abid ; Schneider, Bernard L ; Aebischer, Patrick ; Lashuel, Hilal A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p131t-10eec8c4aeb82e60b37c892fd8aec99aa98c67955739a9343b82416c029f2aff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Kinases</topic><topic>Parkinson's disease</topic><topic>Phosphorylation</topic><topic>Poliomyelitis</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oueslati, Abid</creatorcontrib><creatorcontrib>Schneider, Bernard L</creatorcontrib><creatorcontrib>Aebischer, Patrick</creatorcontrib><creatorcontrib>Lashuel, Hilal A</creatorcontrib><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Toxicology Abstracts</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oueslati, Abid</au><au>Schneider, Bernard L</au><au>Aebischer, Patrick</au><au>Lashuel, Hilal A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><date>2013-10-08</date><risdate>2013</risdate><volume>110</volume><issue>41</issue><spage>E3945</spage><epage>E3945</epage><pages>E3945-E3945</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/ α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. [PUBLICATION ABSTRACT]</abstract><cop>Washington</cop><pub>National Academy of Sciences</pub><doi>10.1073/pnas.1309991110</doi></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0027-8424 |
ispartof | Proceedings of the National Academy of Sciences - PNAS, 2013-10, Vol.110 (41), p.E3945-E3945 |
issn | 0027-8424 1091-6490 |
language | eng |
recordid | cdi_proquest_miscellaneous_1512331841 |
source | JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
subjects | Kinases Parkinson's disease Phosphorylation Poliomyelitis Proteins Rodents Toxicity |
title | Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-11T08%3A39%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Polo-like%20kinase%202%20regulates%20selective%20autophagic%20?-synuclein%20clearance%20and%20suppresses%20its%20toxicity%20in%20vivo&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Oueslati,%20Abid&rft.date=2013-10-08&rft.volume=110&rft.issue=41&rft.spage=E3945&rft.epage=E3945&rft.pages=E3945-E3945&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.1309991110&rft_dat=%3Cproquest%3E1512331841%3C/proquest%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1442584117&rft_id=info:pmid/&rfr_iscdi=true |