Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis
Identifieur interne : 001839 ( Main/Corpus ); précédent : 001838; suivant : 001840Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis
Auteurs : Jessica C. Greene ; Alexander J. Whitworth ; Laurie A. Andrews ; Tracey J. Parker ; Leo J. PallanckSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2005-03-15.
Abstract
Loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase, are a common cause of autosomal recessive juvenile parkinsonism (ARJP). Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly Drosophila melanogaster. In previous work, we demonstrated that Drosophila parkin null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in parkin mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for parkin modifiers. Results of these studies indicate that oxidative stress response components are induced in parkin mutants and that loss-of-function mutations in oxidative stress components enhance the parkin mutant phenotypes. Genes involved in the innate immune response are also induced in parkin mutants. In contrast, our studies did not reveal evidence for cell cycle or ER stress pathway induction in parkin mutants. These results suggest that oxidative stress and/or inflammation may play a fundamental role in the etiology of ARJP.
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DOI: 10.1093/hmg/ddi074
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Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly Drosophila melanogaster. In previous work, we demonstrated that Drosophila parkin null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in parkin mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for parkin modifiers. Results of these studies indicate that oxidative stress response components are induced in parkin mutants and that loss-of-function mutations in oxidative stress components enhance the parkin mutant phenotypes. Genes involved in the innate immune response are also induced in parkin mutants. In contrast, our studies did not reveal evidence for cell cycle or ER stress pathway induction in parkin mutants. These results suggest that oxidative stress and/or inflammation may play a fundamental role in the etiology of ARJP.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Jessica C. Greene</name><affiliations><json:string>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</json:string></affiliations></json:item><json:item><name>Alexander J. Whitworth</name><affiliations><json:string>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</json:string></affiliations></json:item><json:item><name>Laurie A. Andrews</name><affiliations><json:string>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</json:string></affiliations></json:item><json:item><name>Tracey J. Parker</name><affiliations><json:string>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</json:string></affiliations></json:item><json:item><name>Leo J. Pallanck</name><affiliations><json:string>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</json:string><json:string>E-mail: pallanck@gs.washington.edu</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Article</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase, are a common cause of autosomal recessive juvenile parkinsonism (ARJP). Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly Drosophila melanogaster. In previous work, we demonstrated that Drosophila parkin null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in parkin mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for parkin modifiers. Results of these studies indicate that oxidative stress response components are induced in parkin mutants and that loss-of-function mutations in oxidative stress components enhance the parkin mutant phenotypes. Genes involved in the innate immune response are also induced in parkin mutants. In contrast, our studies did not reveal evidence for cell cycle or ER stress pathway induction in parkin mutants. 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Tel: +1 2066165997; Fax: +1 2065430754; Email: pallanck@gs.washington.edu</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis</title><author><persName><forename type="first">Jessica C.</forename><surname>Greene</surname></persName><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation></author><author><persName><forename type="first">Alexander J.</forename><surname>Whitworth</surname></persName><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation></author><author><persName><forename type="first">Laurie A.</forename><surname>Andrews</surname></persName><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation></author><author><persName><forename type="first">Tracey J.</forename><surname>Parker</surname></persName><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation></author><author><persName><forename type="first">Leo J.</forename><surname>Pallanck</surname></persName><email>pallanck@gs.washington.edu</email><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Hum. Mol. Genet.</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-03-15"></date><biblScope unit="volume">14</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="799">799</biblScope><biblScope unit="page" to="811">811</biblScope></imprint></monogr><idno type="istex">11B29F77DEBC4127C3219875E63DA3D4707AEB95</idno><idno type="DOI">10.1093/hmg/ddi074</idno><idno type="href">ddi074</idno><idno type="local">ddi074</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005-02-02</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase, are a common cause of autosomal recessive juvenile parkinsonism (ARJP). Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly Drosophila melanogaster. In previous work, we demonstrated that Drosophila parkin null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in parkin mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for parkin modifiers. Results of these studies indicate that oxidative stress response components are induced in parkin mutants and that loss-of-function mutations in oxidative stress components enhance the parkin mutant phenotypes. Genes involved in the innate immune response are also induced in parkin mutants. In contrast, our studies did not reveal evidence for cell cycle or ER stress pathway induction in parkin mutants. These results suggest that oxidative stress and/or inflammation may play a fundamental role in the etiology of ARJP.</p></abstract></profileDesc><revisionDesc><change when="2005-02-02">Created</change><change when="2005-03-15">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">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/11B29F77DEBC4127C3219875E63DA3D4707AEB95/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</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 xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">Hum. Mol. Genet.</abbrev-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="other">ddi074</article-id><article-id pub-id-type="doi">10.1093/hmg/ddi074</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Genetic and genomic studies of <italic>Drosophila parkin</italic> mutants implicate oxidative stress and innate immune responses in pathogenesis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Greene</surname><given-names>Jessica C.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Whitworth</surname><given-names>Alexander J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Andrews</surname><given-names>Laurie A.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Parker</surname><given-names>Tracey J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Pallanck</surname><given-names>Leo J.</given-names></name><xref rid="COR1">*</xref></contrib><aff>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed. Tel: +1 2066165997; Fax: +1 2065430754; Email: <ext-link xlink:href="pallanck@gs.washington.edu" ext-link-type="email">pallanck@gs.washington.edu</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>2</day><month>02</month><year>2005</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>March</month><year>2005</year></pub-date><volume>14</volume><issue>6</issue><fpage>799</fpage><lpage>811</lpage><history><date date-type="accepted"><day>18</day><month>01</month><year>2005</year></date><date date-type="received"><day>3</day><month>12</month><year>2004</year></date></history><permissions><copyright-statement>© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: <ext-link xlink:href="journals.permissions@oupjournals.org" ext-link-type="email">journals.permissions@oupjournals.org</ext-link></copyright-statement><copyright-year>2005</copyright-year></permissions><self-uri content-type="arthw-pdf" xlink:href="ddi074"></self-uri><abstract xml:lang="en"><p>Loss-of-function mutations of the <italic>parkin</italic> gene, which encodes a ubiquitin-protein ligase, are a common cause of autosomal recessive juvenile parkinsonism (ARJP). Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly <italic>Drosophila melanogaster.</italic> In previous work, we demonstrated that <italic>Drosophila parkin</italic> null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in <italic>parkin</italic> mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for <italic>parkin</italic> modifiers. Results of these studies indicate that oxidative stress response components are induced in <italic>parkin</italic> mutants and that loss-of-function mutations in oxidative stress components enhance the <italic>parkin</italic> mutant phenotypes. Genes involved in the innate immune response are also induced in <italic>parkin</italic> mutants. In contrast, our studies did not reveal evidence for cell cycle or ER stress pathway induction in <italic>parkin</italic> mutants. These results suggest that oxidative stress and/or inflammation may play a fundamental role in the etiology of ARJP.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>799</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>15 March 2005</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis</title></titleInfo><name type="personal"><namePart type="given">Jessica C.</namePart><namePart type="family">Greene</namePart><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexander J.</namePart><namePart type="family">Whitworth</namePart><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurie A.</namePart><namePart type="family">Andrews</namePart><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tracey J.</namePart><namePart type="family">Parker</namePart><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Leo J.</namePart><namePart type="family">Pallanck</namePart><affiliation>Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA</affiliation><affiliation>E-mail: pallanck@gs.washington.edu</affiliation><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">2005-03-15</dateIssued><dateCreated encoding="w3cdtf">2005-02-02</dateCreated><copyrightDate encoding="w3cdtf">2005</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 lang="en">Loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase, are a common cause of autosomal recessive juvenile parkinsonism (ARJP). Previous work has led to the identification of a number of Parkin substrates that implicate specific pathways in ARJP pathogenesis, including endoplasmic reticulum (ER) stress and cell cycle activation. To test the involvement of previously implicated pathways, as well as to identify novel pathways in ARJP pathogenesis, we are using genetic and genomic approaches to study Parkin function in the fruit fly Drosophila melanogaster. In previous work, we demonstrated that Drosophila parkin null mutants exhibit mitochondrial pathology and flight muscle degeneration. To further explore the mechanisms responsible for pathology in parkin mutants, we analyzed the transcriptional alterations that occur during muscle degeneration and performed a genetic screen for parkin modifiers. Results of these studies indicate that oxidative stress response components are induced in parkin mutants and that loss-of-function mutations in oxidative stress components enhance the parkin mutant phenotypes. 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