Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling
Identifieur interne : 001853 ( Pmc/Curation ); précédent : 001852; suivant : 001854Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling
Auteurs : Peter Göttle [Allemagne] ; Jennifer K. Sabo [Australie] ; André Heinen [Allemagne] ; Gene Venables [Australie] ; Klintsy Torres [Allemagne] ; Nevena Tzekova [Allemagne] ; Carlos M. Parras [France] ; David Kremer [Allemagne] ; Hans-Peter Hartung [Allemagne] ; Holly S. Cate [Australie] ; Patrick Küry [Allemagne]Source :
- The Journal of Neuroscience [ 0270-6474 ] ; 2015.
Abstract
Multiple sclerosis is an autoimmune disease of the CNS resulting in degeneration of myelin sheaths and loss of oligodendrocytes, which means that protection and electrical insulation of axons and rapid signal propagation are impaired, leading to axonal damage and permanent disabilities. Partial replacement of lost oligodendrocytes and remyelination can occur as a result of activation and recruitment of resident oligodendroglial precursor cells. However, the overall remyelination capacity remains inefficient because precursor cells often fail to generate new oligodendrocytes. Increasing evidence points to the existence of several molecular inhibitors that act on these cells and interfere with their cellular maturation. The
Url:
DOI: 10.1523/JNEUROSCI.1423-14.2015
PubMed: 25609610
PubMed Central: 4300332
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<series><title level="j">The Journal of Neuroscience</title>
<idno type="ISSN">0270-6474</idno>
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<front><div type="abstract" xml:lang="en"><p>Multiple sclerosis is an autoimmune disease of the CNS resulting in degeneration of myelin sheaths and loss of oligodendrocytes, which means that protection and electrical insulation of axons and rapid signal propagation are impaired, leading to axonal damage and permanent disabilities. Partial replacement of lost oligodendrocytes and remyelination can occur as a result of activation and recruitment of resident oligodendroglial precursor cells. However, the overall remyelination capacity remains inefficient because precursor cells often fail to generate new oligodendrocytes. Increasing evidence points to the existence of several molecular inhibitors that act on these cells and interfere with their cellular maturation. The <italic>p57kip2</italic>
gene encodes one such potent inhibitor of oligodendroglial differentiation and this study sheds light on the underlying mode of action. We found that subcellular distribution of the p57kip2 protein changed during differentiation of rat, mouse, and human oligodendroglial cells both <italic>in vivo</italic>
and <italic>in vitro</italic>
. Nuclear export of p57kip2 was correlated with promoted myelin expression, higher morphological phenotypes, and enhanced myelination <italic>in vitro</italic>
. In contrast, nuclear accumulation of p57kip2 resulted in blocked oligodendroglial differentiation. Experimental evidence suggests that the inhibitory role of p57kip2 depends on specific interactions with binding proteins such as LIMK-1, CDK2, Mash1, and Hes5 either by controlling their site of action or their activity. Because functional restoration in demyelinating diseases critically depends on the successful generation of oligodendroglial cells, a therapeutic need that is currently unmet, the regulatory mechanism described here might be of particular interest for identifying suitable drug targets and devising novel therapeutic approaches.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Neurosci</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Neurosci</journal-id>
<journal-id journal-id-type="hwp">jneuro</journal-id>
<journal-id journal-id-type="pmc">jneurosci</journal-id>
<journal-id journal-id-type="publisher-id">J. Neurosci</journal-id>
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<issn pub-type="ppub">0270-6474</issn>
<issn pub-type="epub">1529-2401</issn>
<publisher><publisher-name>Society for Neuroscience</publisher-name>
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<article-id pub-id-type="doi">10.1523/JNEUROSCI.1423-14.2015</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Articles</subject>
<subj-group><subject>Cellular/Molecular</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Oligodendroglial Maturation Is Dependent on Intracellular Protein Shuttling</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Göttle</surname>
<given-names>Peter</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sabo</surname>
<given-names>Jennifer K.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heinen</surname>
<given-names>André</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Venables</surname>
<given-names>Gene</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Torres</surname>
<given-names>Klintsy</given-names>
</name>
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4231-4123</contrib-id>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tzekova</surname>
<given-names>Nevena</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Parras</surname>
<given-names>Carlos M.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kremer</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hartung</surname>
<given-names>Hans-Peter</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cate</surname>
<given-names>Holly S.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Küry</surname>
<given-names>Patrick</given-names>
</name>
<contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-2654-1126</contrib-id>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<aff id="aff1"><sup>1</sup>
Department of Neurology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany,</aff>
<aff id="aff2"><sup>2</sup>
Department of Anatomy and Neuroscience, University of Melbourne, Parkville, 3010 Victoria, Australia, and</aff>
<aff id="aff3"><sup>3</sup>
Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Inserm U1127, 75013 Paris, France</aff>
</contrib-group>
<author-notes><corresp>Correspondence should be addressed to Patrick Küry, PhD,
<addr-line>Department of Neurology, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.</addr-line>
<email>kuery@uni-duesseldorf.de</email>
</corresp>
<fn fn-type="con"><p>Author contributions: P.G., A.H., H.-P.H., and P.K. designed research; P.G., J.K.S., A.H., G.V., K.T., N.T., C.M.P., H.S.C., and P.K. performed research; P.G., J.K.S., C.M.P., D.K., H.S.C., and P.K. analyzed data; P.G. and P.K. wrote the paper.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>21</day>
<month>1</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>21</day>
<month>1</month>
<year>2015</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<volume>35</volume>
<issue>3</issue>
<fpage>906</fpage>
<lpage>919</lpage>
<history><date date-type="received"><day>7</day>
<month>4</month>
<year>2014</year>
</date>
<date date-type="rev-recd"><day>11</day>
<month>11</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>14</day>
<month>11</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2015 Göttle et al.</copyright-statement>
<copyright-year>2015</copyright-year>
<license license-type="open-access"><license-p>This article is freely available online through the <ext-link ext-link-type="uri" xlink:href="http://www.jneurosci.org/cgi/content/full/35/3/906"><italic>J Neurosci</italic>
</ext-link>
Author Open Choice option.</license-p>
</license>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zns00315000906.pdf"></self-uri>
<abstract><p>Multiple sclerosis is an autoimmune disease of the CNS resulting in degeneration of myelin sheaths and loss of oligodendrocytes, which means that protection and electrical insulation of axons and rapid signal propagation are impaired, leading to axonal damage and permanent disabilities. Partial replacement of lost oligodendrocytes and remyelination can occur as a result of activation and recruitment of resident oligodendroglial precursor cells. However, the overall remyelination capacity remains inefficient because precursor cells often fail to generate new oligodendrocytes. Increasing evidence points to the existence of several molecular inhibitors that act on these cells and interfere with their cellular maturation. The <italic>p57kip2</italic>
gene encodes one such potent inhibitor of oligodendroglial differentiation and this study sheds light on the underlying mode of action. We found that subcellular distribution of the p57kip2 protein changed during differentiation of rat, mouse, and human oligodendroglial cells both <italic>in vivo</italic>
and <italic>in vitro</italic>
. Nuclear export of p57kip2 was correlated with promoted myelin expression, higher morphological phenotypes, and enhanced myelination <italic>in vitro</italic>
. In contrast, nuclear accumulation of p57kip2 resulted in blocked oligodendroglial differentiation. Experimental evidence suggests that the inhibitory role of p57kip2 depends on specific interactions with binding proteins such as LIMK-1, CDK2, Mash1, and Hes5 either by controlling their site of action or their activity. Because functional restoration in demyelinating diseases critically depends on the successful generation of oligodendroglial cells, a therapeutic need that is currently unmet, the regulatory mechanism described here might be of particular interest for identifying suitable drug targets and devising novel therapeutic approaches.</p>
</abstract>
<kwd-group><kwd>inhibitor</kwd>
<kwd>mode of action</kwd>
<kwd>myelin repair</kwd>
<kwd>nuclear export</kwd>
<kwd>p57kip2</kwd>
<kwd>regeneration</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
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