Loading…

Parkin promotes intracellular Aβ1–42 clearance

Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Aβ1–42 fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Par...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics 2009-09, Vol.18 (17), p.3206-3216
Main Authors: Burns, Mark P., Zhang, Lihua, Rebeck, G. William, Querfurth, Henry W., Moussa, Charbel E.-H.
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page 3216
container_issue 17
container_start_page 3206
container_title Human molecular genetics
container_volume 18
creator Burns, Mark P.
Zhang, Lihua
Rebeck, G. William
Querfurth, Henry W.
Moussa, Charbel E.-H.
description Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Aβ1–42 fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human Aβ1–42. Lentiviral constructs encoding either human parkin or human Aβ1–42 were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Aβ1–42 levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human Aβ1–42 levels and Aβ1–42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Aβ1–42 levels. Incubation of Aβ1–42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Aβ–ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Aβ1–42 and demonstrate a protective effect in neurodegenerative diseases with Aβ deposits.
doi_str_mv 10.1093/hmg/ddp258
format article
fullrecord <record><control><sourceid>oup_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2733820</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/hmg/ddp258</oup_id><sourcerecordid>10.1093/hmg/ddp258</sourcerecordid><originalsourceid>FETCH-LOGICAL-i223t-6374dbfccbd1295a1d5dd57de573dcf99bfa32e82cb9404c60de41a19a869c953</originalsourceid><addsrcrecordid>eNpVkE1Kw0AYhgdRbK1uPEE2LmPnPzMboRY1loIuFKSbYTIzaUfzR5KK7ryDN_EgHsKTmNBScfUtvoeHlweAUwTPEZRkvMqXY2srzMQeGCLKYYihIPtgCCWnIZeQD8BR0zxDiDgl0SEYIEkFQVIMAbrX9Ysvgqou87J1TeCLttbGZdk603Uw-f5CPx-fFAcmc7rWhXHH4CDVWeNOtncEHq-vHqZxOL-7uZ1O5qHHmLQhJxG1SWpMYhGWTCPLrGWRdSwi1qRSJqkm2AlsEkkhNRxaR5FGUgsujWRkBC423mqd5M4a1w_LVFX7XNfvqtRe_f8UfqWW5avCESECw05wthXoxugs7df7ZifASCCIGf_jynW1-yKo-raqa6s2bTsu3HC-ad3bjuz6KR6RiKn4aaFm8SVczChUMfkFuZZ88Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Parkin promotes intracellular Aβ1–42 clearance</title><source>Oxford Journals Online</source><creator>Burns, Mark P. ; Zhang, Lihua ; Rebeck, G. William ; Querfurth, Henry W. ; Moussa, Charbel E.-H.</creator><creatorcontrib>Burns, Mark P. ; Zhang, Lihua ; Rebeck, G. William ; Querfurth, Henry W. ; Moussa, Charbel E.-H.</creatorcontrib><description>Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Aβ1–42 fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human Aβ1–42. Lentiviral constructs encoding either human parkin or human Aβ1–42 were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Aβ1–42 levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human Aβ1–42 levels and Aβ1–42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Aβ1–42 levels. Incubation of Aβ1–42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Aβ–ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Aβ1–42 and demonstrate a protective effect in neurodegenerative diseases with Aβ deposits.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddp258</identifier><identifier>PMID: 19483198</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Biological and medical sciences ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; Molecular and cellular biology</subject><ispartof>Human molecular genetics, 2009-09, Vol.18 (17), p.3206-3216</ispartof><rights>The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2009</rights><rights>2009 INIST-CNRS</rights><rights>The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=21810256$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Burns, Mark P.</creatorcontrib><creatorcontrib>Zhang, Lihua</creatorcontrib><creatorcontrib>Rebeck, G. William</creatorcontrib><creatorcontrib>Querfurth, Henry W.</creatorcontrib><creatorcontrib>Moussa, Charbel E.-H.</creatorcontrib><title>Parkin promotes intracellular Aβ1–42 clearance</title><title>Human molecular genetics</title><description>Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Aβ1–42 fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human Aβ1–42. Lentiviral constructs encoding either human parkin or human Aβ1–42 were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Aβ1–42 levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human Aβ1–42 levels and Aβ1–42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Aβ1–42 levels. Incubation of Aβ1–42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Aβ–ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Aβ1–42 and demonstrate a protective effect in neurodegenerative diseases with Aβ deposits.</description><subject>Biological and medical sciences</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Molecular and cellular biology</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNpVkE1Kw0AYhgdRbK1uPEE2LmPnPzMboRY1loIuFKSbYTIzaUfzR5KK7ryDN_EgHsKTmNBScfUtvoeHlweAUwTPEZRkvMqXY2srzMQeGCLKYYihIPtgCCWnIZeQD8BR0zxDiDgl0SEYIEkFQVIMAbrX9Ysvgqou87J1TeCLttbGZdk603Uw-f5CPx-fFAcmc7rWhXHH4CDVWeNOtncEHq-vHqZxOL-7uZ1O5qHHmLQhJxG1SWpMYhGWTCPLrGWRdSwi1qRSJqkm2AlsEkkhNRxaR5FGUgsujWRkBC423mqd5M4a1w_LVFX7XNfvqtRe_f8UfqWW5avCESECw05wthXoxugs7df7ZifASCCIGf_jynW1-yKo-raqa6s2bTsu3HC-ad3bjuz6KR6RiKn4aaFm8SVczChUMfkFuZZ88Q</recordid><startdate>20090901</startdate><enddate>20090901</enddate><creator>Burns, Mark P.</creator><creator>Zhang, Lihua</creator><creator>Rebeck, G. William</creator><creator>Querfurth, Henry W.</creator><creator>Moussa, Charbel E.-H.</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>5PM</scope></search><sort><creationdate>20090901</creationdate><title>Parkin promotes intracellular Aβ1–42 clearance</title><author>Burns, Mark P. ; Zhang, Lihua ; Rebeck, G. William ; Querfurth, Henry W. ; Moussa, Charbel E.-H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i223t-6374dbfccbd1295a1d5dd57de573dcf99bfa32e82cb9404c60de41a19a869c953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Biological and medical sciences</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Molecular and cellular biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Burns, Mark P.</creatorcontrib><creatorcontrib>Zhang, Lihua</creatorcontrib><creatorcontrib>Rebeck, G. William</creatorcontrib><creatorcontrib>Querfurth, Henry W.</creatorcontrib><creatorcontrib>Moussa, Charbel E.-H.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</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>Burns, Mark P.</au><au>Zhang, Lihua</au><au>Rebeck, G. William</au><au>Querfurth, Henry W.</au><au>Moussa, Charbel E.-H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Parkin promotes intracellular Aβ1–42 clearance</atitle><jtitle>Human molecular genetics</jtitle><date>2009-09-01</date><risdate>2009</risdate><volume>18</volume><issue>17</issue><spage>3206</spage><epage>3216</epage><pages>3206-3216</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Aβ1–42 fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human Aβ1–42. Lentiviral constructs encoding either human parkin or human Aβ1–42 were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Aβ1–42 levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human Aβ1–42 levels and Aβ1–42-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Aβ1–42 levels. Incubation of Aβ1–42 cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Aβ–ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Aβ1–42 and demonstrate a protective effect in neurodegenerative diseases with Aβ deposits.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>19483198</pmid><doi>10.1093/hmg/ddp258</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0964-6906
ispartof Human molecular genetics, 2009-09, Vol.18 (17), p.3206-3216
issn 0964-6906
1460-2083
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2733820
source Oxford Journals Online
subjects Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Molecular and cellular biology
title Parkin promotes intracellular Aβ1–42 clearance
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T20%3A57%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-oup_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Parkin%20promotes%20intracellular%20A%CE%B21%E2%80%9342%20clearance&rft.jtitle=Human%20molecular%20genetics&rft.au=Burns,%20Mark%20P.&rft.date=2009-09-01&rft.volume=18&rft.issue=17&rft.spage=3206&rft.epage=3216&rft.pages=3206-3216&rft.issn=0964-6906&rft.eissn=1460-2083&rft_id=info:doi/10.1093/hmg/ddp258&rft_dat=%3Coup_pubme%3E10.1093/hmg/ddp258%3C/oup_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-i223t-6374dbfccbd1295a1d5dd57de573dcf99bfa32e82cb9404c60de41a19a869c953%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/19483198&rft_oup_id=10.1093/hmg/ddp258&rfr_iscdi=true