MAP1B rescues LRRK2 mutant-mediated cytotoxicity
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson's disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 int...
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| Veröffentlicht in: | Molecular brain 2014-04, Vol.7 (1), p.29-29 |
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| creator | Chan, Sharon L Chua, Ling-Ling Angeles, Dario C Tan, Eng-King |
| description | Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson's disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases. |
| doi_str_mv | 10.1186/1756-6606-7-29 |
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Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases.</description><identifier>ISSN: 1756-6606</identifier><identifier>EISSN: 1756-6606</identifier><identifier>DOI: 10.1186/1756-6606-7-29</identifier><identifier>PMID: 24754922</identifier><language>eng</language><publisher>England: BioMed Central Ltd</publisher><subject>Apoptosis ; Cell Death ; Cell Line ; Cloning ; Complications and side effects ; Cytotoxicity ; Development and progression ; Experiments ; Genetic aspects ; Humans ; Kinases ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Microtubule-Associated Proteins - metabolism ; Mutant Proteins - metabolism ; Nervous system diseases ; Neurosciences ; Patient outcomes ; Phosphorylation ; Protein Binding ; Protein expression ; Protein Transport ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Risk factors ; Short Report ; Two-Hybrid System Techniques ; Yeast</subject><ispartof>Molecular brain, 2014-04, Vol.7 (1), p.29-29</ispartof><rights>COPYRIGHT 2014 BioMed Central Ltd.</rights><rights>2014 Chan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>Copyright © 2014 Chan et al.; licensee BioMed Central Ltd. 2014 Chan et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b576t-264334c7eae13a8eafbdfa6d3e62b71c2becc7c7f14309f70b70eb56d24064173</citedby><cites>FETCH-LOGICAL-b576t-264334c7eae13a8eafbdfa6d3e62b71c2becc7c7f14309f70b70eb56d24064173</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/PMC4022373/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022373/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24754922$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chan, Sharon L</creatorcontrib><creatorcontrib>Chua, Ling-Ling</creatorcontrib><creatorcontrib>Angeles, Dario C</creatorcontrib><creatorcontrib>Tan, Eng-King</creatorcontrib><title>MAP1B rescues LRRK2 mutant-mediated cytotoxicity</title><title>Molecular brain</title><addtitle>Mol Brain</addtitle><description>Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson's disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases.</description><subject>Apoptosis</subject><subject>Cell Death</subject><subject>Cell Line</subject><subject>Cloning</subject><subject>Complications and side effects</subject><subject>Cytotoxicity</subject><subject>Development and progression</subject><subject>Experiments</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Kinases</subject><subject>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Mutant Proteins - metabolism</subject><subject>Nervous system diseases</subject><subject>Neurosciences</subject><subject>Patient outcomes</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein expression</subject><subject>Protein Transport</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Risk factors</subject><subject>Short Report</subject><subject>Two-Hybrid System Techniques</subject><subject>Yeast</subject><issn>1756-6606</issn><issn>1756-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNks9LHDEUx0OpVKu9eiwLvfQy9uX3zqWwSm1LVxTRc8hk3mhkZmInmdL9781U3Wq1IDkkvPfNh8cnIWSXwh6lc_WJaqkKpUAVumDlK7K1Lrx-cN4kb2O8AlBMUfmGbDKhpSgZ2yJwtDih-7MBoxsxzpanpz_YrBuT7VPRYe1twnrmVimk8Ns7n1Y7ZKOxbcR3d_s2OT_8cnbwrVgef_1-sFgWldQqFUwJzoXTaJFyO0fbVHVjVc1RsUpTxyp0TjvdUMGhbDRUGrCSqmYClKCab5PPt9zrscqDOOzTYFtzPfjODisTrDePO72_NBfhlxHAGNc8Axa3gMqH_wAed1zozGTMTMaMNqzMjI93QwzhZ_aTTOejw7a1PYYxGiqZEACawwuitGQKhJyoH_6JXoVx6LPNPymAUmn6N3VhWzS-b0Ke0k1Qs5BZkpR8PrH2nknlVWPnXeix8bn-3AU3hBgHbNZGKJjpSz118P7hQ6zj93-I3wAgBcQD</recordid><startdate>20140422</startdate><enddate>20140422</enddate><creator>Chan, Sharon L</creator><creator>Chua, Ling-Ling</creator><creator>Angeles, Dario C</creator><creator>Tan, Eng-King</creator><general>BioMed Central Ltd</general><general>BioMed Central</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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</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>CCPQU</scope><scope>DWQXO</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>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140422</creationdate><title>MAP1B rescues LRRK2 mutant-mediated cytotoxicity</title><author>Chan, Sharon L ; Chua, Ling-Ling ; Angeles, Dario C ; Tan, Eng-King</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b576t-264334c7eae13a8eafbdfa6d3e62b71c2becc7c7f14309f70b70eb56d24064173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Apoptosis</topic><topic>Cell Death</topic><topic>Cell Line</topic><topic>Cloning</topic><topic>Complications and side effects</topic><topic>Cytotoxicity</topic><topic>Development and progression</topic><topic>Experiments</topic><topic>Genetic aspects</topic><topic>Humans</topic><topic>Kinases</topic><topic>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Mutant Proteins - metabolism</topic><topic>Nervous system diseases</topic><topic>Neurosciences</topic><topic>Patient outcomes</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein expression</topic><topic>Protein Transport</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Risk factors</topic><topic>Short Report</topic><topic>Two-Hybrid System Techniques</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chan, Sharon L</creatorcontrib><creatorcontrib>Chua, Ling-Ling</creatorcontrib><creatorcontrib>Angeles, Dario C</creatorcontrib><creatorcontrib>Tan, Eng-King</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular brain</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chan, Sharon L</au><au>Chua, Ling-Ling</au><au>Angeles, Dario C</au><au>Tan, Eng-King</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MAP1B rescues LRRK2 mutant-mediated cytotoxicity</atitle><jtitle>Molecular brain</jtitle><addtitle>Mol Brain</addtitle><date>2014-04-22</date><risdate>2014</risdate><volume>7</volume><issue>1</issue><spage>29</spage><epage>29</epage><pages>29-29</pages><issn>1756-6606</issn><eissn>1756-6606</eissn><abstract>Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson's disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases.</abstract><cop>England</cop><pub>BioMed Central Ltd</pub><pmid>24754922</pmid><doi>10.1186/1756-6606-7-29</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Cell Death Cell Line Cloning Complications and side effects Cytotoxicity Development and progression Experiments Genetic aspects Humans Kinases Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Microtubule-Associated Proteins - metabolism Mutant Proteins - metabolism Nervous system diseases Neurosciences Patient outcomes Phosphorylation Protein Binding Protein expression Protein Transport Protein-Serine-Threonine Kinases - metabolism Proteins Risk factors Short Report Two-Hybrid System Techniques Yeast |
| title | MAP1B rescues LRRK2 mutant-mediated cytotoxicity |
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