Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy
Identifieur interne : 001299 ( Istex/Corpus ); précédent : 001298; suivant : 001300Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy
Auteurs : Fiona M. Menzies ; Raphael Hourez ; Sara Imarisio ; Marcel Raspe ; Oana Sadiq ; Dhia Chandraratna ; Cahir O'Kane ; Kenneth L. Rock ; Eric Reits ; Alfred L. Goldberg ; David C. RubinszteinSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-12-01.
Abstract
A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant -synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.
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DOI: 10.1093/hmg/ddq385
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Menzies</name><affiliation><mods:affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</mods:affiliation></affiliation></author><author><name sortKey="Hourez, Raphael" sort="Hourez, Raphael" uniqKey="Hourez R" first="Raphael" last="Hourez">Raphael Hourez</name><affiliation><mods:affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</mods:affiliation></affiliation></author><author><name sortKey="Imarisio, Sara" sort="Imarisio, Sara" uniqKey="Imarisio S" first="Sara" last="Imarisio">Sara Imarisio</name><affiliation><mods:affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</mods:affiliation></affiliation></author><author><name sortKey="Raspe, Marcel" sort="Raspe, Marcel" uniqKey="Raspe M" first="Marcel" last="Raspe">Marcel Raspe</name><affiliation><mods:affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</mods:affiliation></affiliation></author><author><name sortKey="Sadiq, Oana" sort="Sadiq, Oana" uniqKey="Sadiq O" first="Oana" last="Sadiq">Oana Sadiq</name><affiliation><mods:affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</mods:affiliation></affiliation></author><author><name sortKey="Chandraratna, Dhia" sort="Chandraratna, Dhia" uniqKey="Chandraratna D" first="Dhia" last="Chandraratna">Dhia Chandraratna</name><affiliation><mods:affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</mods:affiliation></affiliation></author><author><name sortKey="O Kane, Cahir" sort="O Kane, Cahir" uniqKey="O Kane C" first="Cahir" last="O'Kane">Cahir O'Kane</name><affiliation><mods:affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</mods:affiliation></affiliation></author><author><name sortKey="Rock, Kenneth L" sort="Rock, Kenneth L" uniqKey="Rock K" first="Kenneth L." last="Rock">Kenneth L. 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Menzies</name><affiliation><mods:affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</mods:affiliation></affiliation></author><author><name sortKey="Hourez, Raphael" sort="Hourez, Raphael" uniqKey="Hourez R" first="Raphael" last="Hourez">Raphael Hourez</name><affiliation><mods:affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</mods:affiliation></affiliation></author><author><name sortKey="Imarisio, Sara" sort="Imarisio, Sara" uniqKey="Imarisio S" first="Sara" last="Imarisio">Sara Imarisio</name><affiliation><mods:affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</mods:affiliation></affiliation></author><author><name sortKey="Raspe, Marcel" sort="Raspe, Marcel" uniqKey="Raspe M" first="Marcel" last="Raspe">Marcel Raspe</name><affiliation><mods:affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</mods:affiliation></affiliation></author><author><name sortKey="Sadiq, Oana" sort="Sadiq, Oana" uniqKey="Sadiq O" first="Oana" last="Sadiq">Oana Sadiq</name><affiliation><mods:affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</mods:affiliation></affiliation></author><author><name sortKey="Chandraratna, Dhia" sort="Chandraratna, Dhia" uniqKey="Chandraratna D" first="Dhia" last="Chandraratna">Dhia Chandraratna</name><affiliation><mods:affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</mods:affiliation></affiliation></author><author><name sortKey="O Kane, Cahir" sort="O Kane, Cahir" uniqKey="O Kane C" first="Cahir" last="O'Kane">Cahir O'Kane</name><affiliation><mods:affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</mods:affiliation></affiliation></author><author><name sortKey="Rock, Kenneth L" sort="Rock, Kenneth L" uniqKey="Rock K" first="Kenneth L." last="Rock">Kenneth L. Rock</name><affiliation><mods:affiliation>Pathology Department, University of Massachusetts Medical School, Worcester, USA</mods:affiliation></affiliation></author><author><name sortKey="Reits, Eric" sort="Reits, Eric" uniqKey="Reits E" first="Eric" last="Reits">Eric Reits</name><affiliation><mods:affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</mods:affiliation></affiliation></author><author><name sortKey="Goldberg, Alfred L" sort="Goldberg, Alfred L" uniqKey="Goldberg A" first="Alfred L." last="Goldberg">Alfred L. Goldberg</name><affiliation><mods:affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</mods:affiliation></affiliation></author><author><name sortKey="Rubinsztein, David C" sort="Rubinsztein, David C" uniqKey="Rubinsztein D" first="David C." last="Rubinsztein">David C. Rubinsztein</name><affiliation><mods:affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: dcr1000@cam.ac.uk</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-12-01">2010-12-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">23</biblScope><biblScope unit="page" from="4573">4573</biblScope><biblScope unit="page" to="4586">4586</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">471DAB3F29908A6969C47F55A3B6333FBA33A1D0</idno><idno type="DOI">10.1093/hmg/ddq385</idno><idno type="href">ddq385.pdf</idno><idno type="ArticleID">ddq385</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant -synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Fiona M. 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Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant -synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. 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Published by Oxford University Press.</p></availability><date>2010-09-09</date></publicationStmt><notesStmt><note>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy</title><author xml:id="author-1"><persName><forename type="first">Fiona M.</forename><surname>Menzies</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</affiliation><affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</affiliation></author><author xml:id="author-2"><persName><forename type="first">Raphael</forename><surname>Hourez</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</affiliation><affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</affiliation></author><author xml:id="author-3"><persName><forename type="first">Sara</forename><surname>Imarisio</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</note><affiliation>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</affiliation><affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</affiliation></author><author xml:id="author-4"><persName><forename type="first">Marcel</forename><surname>Raspe</surname></persName><affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</affiliation></author><author xml:id="author-5"><persName><forename type="first">Oana</forename><surname>Sadiq</surname></persName><affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</affiliation></author><author xml:id="author-6"><persName><forename type="first">Dhia</forename><surname>Chandraratna</surname></persName><affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</affiliation></author><author xml:id="author-7"><persName><forename type="first">Cahir</forename><surname>O'Kane</surname></persName><affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</affiliation></author><author xml:id="author-8"><persName><forename type="first">Kenneth L.</forename><surname>Rock</surname></persName><affiliation>Pathology Department, University of Massachusetts Medical School, Worcester, USA</affiliation></author><author xml:id="author-9"><persName><forename type="first">Eric</forename><surname>Reits</surname></persName><affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</affiliation></author><author xml:id="author-10"><persName><forename type="first">Alfred L.</forename><surname>Goldberg</surname></persName><note type="biography">These two authors should be regarded as Senior Authors.</note><affiliation>These two authors should be regarded as Senior Authors.</affiliation><affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</affiliation></author><author xml:id="author-11"><persName><forename type="first">David C.</forename><surname>Rubinsztein</surname></persName><email>dcr1000@cam.ac.uk</email><note type="biography">These two authors should be regarded as Senior Authors.</note><affiliation>These two authors should be regarded as Senior Authors.</affiliation><affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-12-01"></date><biblScope unit="volume">19</biblScope><biblScope unit="issue">23</biblScope><biblScope unit="page" from="4573">4573</biblScope><biblScope unit="page" to="4586">4586</biblScope></imprint></monogr><idno type="istex">471DAB3F29908A6969C47F55A3B6333FBA33A1D0</idno><idno type="DOI">10.1093/hmg/ddq385</idno><idno type="href">ddq385.pdf</idno><idno type="ArticleID">ddq385</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-09-09</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant -synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.</p></abstract></profileDesc><revisionDesc><change when="2010-09-09">Created</change><change when="2010-12-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/471DAB3F29908A6969C47F55A3B6333FBA33A1D0/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddq385</article-id><article-id pub-id-type="publisher-id">ddq385</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Menzies</surname><given-names>Fiona M.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="fn" rid="AN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Hourez</surname><given-names>Raphael</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="fn" rid="AN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Imarisio</surname><given-names>Sara</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="fn" rid="AN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Raspe</surname><given-names>Marcel</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Sadiq</surname><given-names>Oana</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chandraratna</surname><given-names>Dhia</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>O'Kane</surname><given-names>Cahir</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Rock</surname><given-names>Kenneth L.</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Reits</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Goldberg</surname><given-names>Alfred L.</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="fn" rid="AN2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Rubinsztein</surname><given-names>David C.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref><xref ref-type="fn" rid="AN2">‡</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Medical Genetics, Cambridge Institute for Medical Research</addr-line> and</aff><aff id="af2"><label>2</label><addr-line>Department of Genetics</addr-line>, <institution>University of Cambridge</institution>, <addr-line>Cambridge</addr-line>, <country>UK</country>,</aff><aff id="af3"><label>3</label><addr-line>Department of Cell Biology</addr-line>, <institution>Harvard Medical School</institution>, <addr-line>Boston</addr-line>, <country>USA</country>,</aff><aff id="af4"><label>4</label><addr-line>Department of Cell Biology and Histology, Academic Medical Centre</addr-line>, <institution>University of Amsterdam</institution>, <addr-line>Amsterdam</addr-line>, <country>The Netherlands</country> and</aff><aff id="af5"><label>5</label><addr-line>Pathology Department</addr-line>, <institution>University of Massachusetts Medical School</institution>, <addr-line>Worcester</addr-line>, <country>USA</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Email: <email>dcr1000@cam.ac.uk</email></corresp><fn fn-type="con" id="AN1"><label>†</label><p>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</p></fn><fn fn-type="con" id="AN2"><label>‡</label><p>These two authors should be regarded as Senior Authors.</p></fn></author-notes><pub-date pub-type="ppub"><day>1</day><month>12</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>9</day><month>9</month><year>2010</year></pub-date><volume>19</volume><issue>23</issue><fpage>4573</fpage><lpage>4586</lpage><history><date date-type="received"><day>1</day><month>6</month><year>2010</year></date><date date-type="rev-recd"><day>16</day><month>8</month><year>2010</year></date><date date-type="accepted"><day>3</day><month>9</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press.</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.5/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license></permissions><self-uri content-type="pdf" xlink:href="ddq385.pdf"></self-uri><abstract><p>A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, <italic>Drosophila</italic> and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant &agr;-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy</title></titleInfo><name type="personal"><namePart type="given">Fiona M.</namePart><namePart type="family">Menzies</namePart><affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</affiliation><description>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Raphael</namePart><namePart type="family">Hourez</namePart><affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</affiliation><description>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sara</namePart><namePart type="family">Imarisio</namePart><affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</affiliation><description>The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marcel</namePart><namePart type="family">Raspe</namePart><affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Oana</namePart><namePart type="family">Sadiq</namePart><affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dhia</namePart><namePart type="family">Chandraratna</namePart><affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cahir</namePart><namePart type="family">O'Kane</namePart><affiliation>Department of Genetics, University of Cambridge, Cambridge, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kenneth L.</namePart><namePart type="family">Rock</namePart><affiliation>Pathology Department, University of Massachusetts Medical School, Worcester, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eric</namePart><namePart type="family">Reits</namePart><affiliation>Department of Cell Biology and Histology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alfred L.</namePart><namePart type="family">Goldberg</namePart><affiliation>Department of Cell Biology, Harvard Medical School, Boston, USA,</affiliation><description>These two authors should be regarded as Senior Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David C.</namePart><namePart type="family">Rubinsztein</namePart><affiliation>Department of Medical Genetics, Cambridge Institute for Medical Research and</affiliation><affiliation>E-mail: dcr1000@cam.ac.uk</affiliation><description>These two authors should be regarded as Senior Authors.</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-12-01</dateIssued><dateCreated encoding="w3cdtf">2010-09-09</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant -synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.</abstract><note type="footnotes">The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>23</number></detail><extent unit="pages"><start>4573</start><end>4586</end></extent></part></relatedItem><identifier type="istex">471DAB3F29908A6969C47F55A3B6333FBA33A1D0</identifier><identifier type="DOI">10.1093/hmg/ddq385</identifier><identifier type="href">ddq385.pdf</identifier><identifier type="ArticleID">ddq385</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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