Modest loss of peripheral axons and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1
Identifieur interne : 000B64 ( Pmc/Checkpoint ); précédent : 000B63; suivant : 000B65Modest loss of peripheral axons and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1
Auteurs : Florence Dequen [Canada] ; Pascale Bomont [États-Unis, France] ; Geneviève Gowing [Canada] ; Don W. Cleveland [États-Unis] ; Jean-Pierre Julien [Canada]Source :
- Journal of neurochemistry [ 0022-3042 ] ; 2008.
Abstract
Mutations in gigaxonin are responsible for Giant Axonal Neuropathy (GAN), a progressive neurodegenerative disorder associated with abnormal accumulations of Intermediate Filaments (IFs). Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and TBCB. Here, we report the generation of a mouse model with targeted deletion of
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DOI: 10.1111/j.1471-4159.2008.05601.x
PubMed: 18680552
PubMed Central: 3657508
Affiliations:
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PMC:3657508Le document en format XML
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<front><div type="abstract" xml:lang="en"><p id="P1">Mutations in gigaxonin are responsible for Giant Axonal Neuropathy (GAN), a progressive neurodegenerative disorder associated with abnormal accumulations of Intermediate Filaments (IFs). Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and TBCB. Here, we report the generation of a mouse model with targeted deletion of <italic>Gan</italic>
exon 1 (<italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
). Analyses of the <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice revealed increased levels of various IFs proteins in nervous system and the presence of IFs inclusion bodies in the brain. Despite deficiency of full length gigaxonin, the <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease. We propose that the existence of a short gigaxonin isoform expressed in the spinal cord could underlie the mitigation of GAN-phenotypes in <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice. Nonetheless, the <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice exhibited modest increase in axon calibers and 27% axonal loss in the L5 ventral roots. This new mouse model should provide a useful tool for testing potential therapeutic approaches for GAN disease.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">2985190R</journal-id>
<journal-id journal-id-type="pubmed-jr-id">5004</journal-id>
<journal-id journal-id-type="nlm-ta">J Neurochem</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Neurochem.</journal-id>
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<article-id pub-id-type="manuscript">NIHMS453469</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<title-group><article-title>Modest loss of peripheral axons and formation of brain inclusions in mice with targeted deletion of gigaxonin exon 1</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Dequen</surname>
<given-names>Florence</given-names>
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<xref ref-type="aff" rid="A1">1</xref>
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<contrib contrib-type="author"><name><surname>Bomont</surname>
<given-names>Pascale</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A4">4</xref>
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<contrib contrib-type="author"><name><surname>Gowing</surname>
<given-names>Geneviève</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cleveland</surname>
<given-names>Don W.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Julien</surname>
<given-names>Jean-Pierre</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
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<aff id="A1"><label>1</label>
CHUL Research Centre and Department of Anatomy and Physiology, Laval University, Québec, Canada</aff>
<aff id="A2"><label>2</label>
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA</aff>
<aff id="A3"><label>3</label>
Inserm, U29, INMED, Marseille, F-13009, France</aff>
<aff id="A4"><label>4</label>
Aix Marseille Université, Faculté des Sciences, Marseille, F-13009, France</aff>
<author-notes><corresp id="FN1">To whom correspondence should be addressed: Dr. Jean-Pierre Julien, CHUL Research Centre, 2705, Laurier Boulevard, Sainte-Foy, Pavillon T2-41, Quebec, Canada, G1V 4G2, Tel : (418) 654-2296 ; Fax : (418) 654-2761, <email>jean-pierre.julien@crchul.ulaval.ca</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>26</day>
<month>4</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>31</day>
<month>7</month>
<year>2008</year>
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<pub-date pub-type="ppub"><month>10</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>19</day>
<month>5</month>
<year>2013</year>
</pub-date>
<volume>107</volume>
<issue>1</issue>
<fpage>253</fpage>
<lpage>264</lpage>
<abstract><p id="P1">Mutations in gigaxonin are responsible for Giant Axonal Neuropathy (GAN), a progressive neurodegenerative disorder associated with abnormal accumulations of Intermediate Filaments (IFs). Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and TBCB. Here, we report the generation of a mouse model with targeted deletion of <italic>Gan</italic>
exon 1 (<italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
). Analyses of the <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice revealed increased levels of various IFs proteins in nervous system and the presence of IFs inclusion bodies in the brain. Despite deficiency of full length gigaxonin, the <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice do not develop overt neurological phenotypes and giant axons reminiscent of the human GAN disease. We propose that the existence of a short gigaxonin isoform expressed in the spinal cord could underlie the mitigation of GAN-phenotypes in <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice. Nonetheless, the <italic>Gan<sup>Δexon1;Δexon1</sup>
</italic>
mice exhibited modest increase in axon calibers and 27% axonal loss in the L5 ventral roots. This new mouse model should provide a useful tool for testing potential therapeutic approaches for GAN disease.</p>
</abstract>
<kwd-group><kwd>intermediate filaments</kwd>
<kwd>inclusion bodies</kwd>
<kwd>neuropathy</kwd>
</kwd-group>
<funding-group><award-group><funding-source country="United States">National Institute of Neurological Disorders and Stroke : NINDS</funding-source>
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