Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease
Identifieur interne : 002772 ( Main/Corpus ); précédent : 002771; suivant : 002773Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease
Auteurs : Catherine Kielar ; Thomas M. Wishart ; Alice Palmer ; Sybille Dihanich ; Andrew M. Wong ; Shannon L. Macauley ; Chun-Hung Chan ; Mark S. Sands ; David A. Pearce ; Jonathan D. Cooper ; Thomas H. GillingwaterSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-11-01.
Abstract
Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1/ model of infantile NCL and Cln6nclf model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.
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DOI: 10.1093/hmg/ddp355
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Gillingwater</name><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: t.gillingwater@ed.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="2009-11-01">2009-11-01</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">21</biblScope><biblScope unit="page" from="4066">4066</biblScope><biblScope unit="page" to="4080">4080</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">66192E28B1A3966517E8D1E3289579D89F041C8E</idno><idno type="DOI">10.1093/hmg/ddp355</idno><idno type="ArticleID">ddp355</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">Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1/ model of infantile NCL and Cln6nclf model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Catherine Kielar</name><affiliations><json:string>Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK</json:string></affiliations></json:item><json:item><name>Thomas M. Wishart</name><affiliations><json:string>Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh EH8 9XD, UK</json:string></affiliations></json:item><json:item><name>Alice Palmer</name><affiliations><json:string>Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh EH8 9XD, UK</json:string></affiliations></json:item><json:item><name>Sybille Dihanich</name><affiliations><json:string>Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK</json:string></affiliations></json:item><json:item><name>Andrew M. Wong</name><affiliations><json:string>Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK</json:string></affiliations></json:item><json:item><name>Shannon L. Macauley</name><affiliations><json:string>Department of Internal Medicine</json:string><json:string>Department of Genetics, Washington University School of Medicine, St Louis, MO, USA</json:string></affiliations></json:item><json:item><name>Chun-Hung Chan</name><affiliations><json:string>Centre for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA</json:string></affiliations></json:item><json:item><name>Mark S. Sands</name><affiliations><json:string>Department of Internal Medicine</json:string><json:string>Department of Genetics, Washington University School of Medicine, St Louis, MO, USA</json:string></affiliations></json:item><json:item><name>David A. Pearce</name><affiliations><json:string>Centre for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA</json:string></affiliations></json:item><json:item><name>Jonathan D. Cooper</name><affiliations><json:string>Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK</json:string></affiliations></json:item><json:item><name>Thomas H. Gillingwater</name><affiliations><json:string>Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh EH8 9XD, UK</json:string><json:string>E-mail: t.gillingwater@ed.ac.uk</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ARTICLES</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1/ model of infantile NCL and Cln6nclf model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.</abstract><qualityIndicators><score>8.976</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>1</keywordCount><abstractCharCount>1778</abstractCharCount><pdfWordCount>8972</pdfWordCount><pdfCharCount>58263</pdfCharCount><pdfPageCount>15</pdfPageCount><abstractWordCount>248</abstractWordCount></qualityIndicators><title>Molecular correlates of axonal and synaptic pathology in mouse models of Batten 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M.</forename><surname>Wishart</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</note><affiliation>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</affiliation><affiliation></affiliation></author><author><persName><forename type="first">Alice</forename><surname>Palmer</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Sybille</forename><surname>Dihanich</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Andrew M.</forename><surname>Wong</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Shannon L.</forename><surname>Macauley</surname></persName><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">Chun-Hung</forename><surname>Chan</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Mark S.</forename><surname>Sands</surname></persName><affiliation></affiliation><affiliation></affiliation></author><author><persName><forename type="first">David A.</forename><surname>Pearce</surname></persName><affiliation></affiliation></author><author><persName><forename type="first">Jonathan D.</forename><surname>Cooper</surname></persName><note type="biography">The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</note><affiliation>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</affiliation><affiliation></affiliation></author><author><persName><forename type="first">Thomas H.</forename><surname>Gillingwater</surname></persName><email>t.gillingwater@ed.ac.uk</email><note type="biography">The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</note><affiliation>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</affiliation><affiliation></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="2009-11-01"></date><biblScope unit="volume">18</biblScope><biblScope unit="issue">21</biblScope><biblScope unit="page" from="4066">4066</biblScope><biblScope unit="page" to="4080">4080</biblScope></imprint></monogr><idno type="istex">66192E28B1A3966517E8D1E3289579D89F041C8E</idno><idno type="DOI">10.1093/hmg/ddp355</idno><idno type="ArticleID">ddp355</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-07-29</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1/ model of infantile NCL and Cln6nclf model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.</p></abstract></profileDesc><revisionDesc><change when="2009-07-29">Created</change><change when="2009-11-01">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/66192E28B1A3966517E8D1E3289579D89F041C8E/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/ddp355</article-id><article-id pub-id-type="publisher-id">ddp355</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kielar</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="fn" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Wishart</surname><given-names>Thomas M.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="fn" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Palmer</surname><given-names>Alice</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Dihanich</surname><given-names>Sybille</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Andrew M.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Macauley</surname><given-names>Shannon L.</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Chan</surname><given-names>Chun-Hung</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Sands</surname><given-names>Mark S.</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Pearce</surname><given-names>David A.</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>Jonathan D.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="fn" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Gillingwater</surname><given-names>Thomas H.</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref><xref ref-type="fn" rid="FN1">†</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Neuroscience</addr-line>, <institution>Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London</institution>, <addr-line>London SE5 9NU</addr-line>, <country>UK</country></aff><aff id="af2"><label>2</label><addr-line>Centre for Integrative Physiology</addr-line>, <institution>University of Edinburgh Medical School</institution>, <addr-line>Edinburgh EH8 9XD</addr-line>, <country>UK</country></aff><aff id="af3"><label>3</label><addr-line>Department of Internal Medicine</addr-line></aff><aff id="af4"><label>4</label><addr-line>Department of Genetics</addr-line>, <institution>Washington University School of Medicine</institution>, <addr-line>St Louis, MO</addr-line>, <country>USA</country></aff><aff id="af5"><label>5</label><addr-line>Centre for Neural Development and Disease</addr-line>, <institution>University of Rochester School of Medicine and Dentistry</institution>, <addr-line>Rochester, New York 14642</addr-line>, <country>USA</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+44 1316503724</phone>; Fax: <fax>+44 1316504193</fax>; Email: <email>t.gillingwater@ed.ac.uk</email></corresp><fn id="FN1"><label>†</label><p>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</p></fn></author-notes><pub-date pub-type="ppub"><day>1</day><month>11</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>29</day><month>7</month><year>2009</year></pub-date><volume>18</volume><issue>21</issue><fpage>4066</fpage><lpage>4080</lpage><history><date date-type="received"><day>25</day><month>6</month><year>2009</year></date><date date-type="accepted"><day>26</day><month>7</month><year>2009</year></date></history><copyright-statement>© 2009 The Author(s).</copyright-statement><copyright-year>2009</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><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/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: <italic>Ppt1</italic><sup><italic>−/−</italic></sup> model of infantile NCL and <italic>Cln6</italic><sup><italic>nclf</italic></sup> model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as <italic>in vivo</italic> biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease</title></titleInfo><name type="personal"><namePart type="given">Catherine</namePart><namePart type="family">Kielar</namePart><affiliation></affiliation><description>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas M.</namePart><namePart type="family">Wishart</namePart><affiliation></affiliation><description>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alice</namePart><namePart type="family">Palmer</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sybille</namePart><namePart type="family">Dihanich</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrew M.</namePart><namePart type="family">Wong</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shannon L.</namePart><namePart type="family">Macauley</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chun-Hung</namePart><namePart type="family">Chan</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark S.</namePart><namePart type="family">Sands</namePart><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David A.</namePart><namePart type="family">Pearce</namePart><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jonathan D.</namePart><namePart type="family">Cooper</namePart><affiliation></affiliation><description>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas H.</namePart><namePart type="family">Gillingwater</namePart><affiliation></affiliation><affiliation>E-mail: t.gillingwater@ed.ac.uk</affiliation><description>The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</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">2009-11-01</dateIssued><dateCreated encoding="w3cdtf">2009-07-29</dateCreated><copyrightDate encoding="w3cdtf">2009</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>Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1/ model of infantile NCL and Cln6nclf model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.</abstract><note type="footnotes">The authors wish it to be known that, in their opinion, these authors contributed equally to this study.</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>2009</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><detail type="issue"><caption>no.</caption><number>21</number></detail><extent unit="pages"><start>4066</start><end>4080</end></extent></part></relatedItem><identifier type="istex">66192E28B1A3966517E8D1E3289579D89F041C8E</identifier><identifier type="DOI">10.1093/hmg/ddp355</identifier><identifier type="ArticleID">ddp355</identifier><accessCondition type="use and reproduction" contentType="copyright">2009 The Author(s).</accessCondition><recordInfo><recordContentSource>OUP</recordContentSource></recordInfo></mods></metadata><covers><json:item><original>true</original><mimetype>image/tiff</mimetype><extension>tiff</extension><uri>https://api.istex.fr/document/66192E28B1A3966517E8D1E3289579D89F041C8E/covers/tiff</uri></json:item><json:item><original>true</original><mimetype>text/html</mimetype><extension>html</extension><uri>https://api.istex.fr/document/66192E28B1A3966517E8D1E3289579D89F041C8E/covers/html</uri></json:item></covers><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/66192E28B1A3966517E8D1E3289579D89F041C8E/annexes/jpeg</uri></json:item><json:item><original>true</original><mimetype>image/gif</mimetype><extension>gif</extension><uri>https://api.istex.fr/document/66192E28B1A3966517E8D1E3289579D89F041C8E/annexes/gif</uri></json:item></annexes><enrichments><istex:catWosTEI uri="https://api.istex.fr/document/66192E28B1A3966517E8D1E3289579D89F041C8E/enrichments/catWos"><teiHeader><profileDesc><textClass><classCode scheme="WOS">BIOCHEMISTRY & MOLECULAR BIOLOGY</classCode><classCode scheme="WOS">GENETICS & HEREDITY</classCode></textClass></profileDesc></teiHeader></istex:catWosTEI></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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