Mutant HSPB8 causes motor neuron-specific neurite degeneration
Identifieur interne : 001226 ( Istex/Corpus ); précédent : 001225; suivant : 001227Mutant HSPB8 causes motor neuron-specific neurite degeneration
Auteurs : Joy Irobi ; Leonardo Almeida-Souza ; Bob Asselbergh ; Vicky De Winter ; Sofie Goethals ; Ines Dierick ; Jyothsna Krishnan ; Jean-Pierre Timmermans ; Wim Robberecht ; Peter De Jonghe ; Ludo Van Den Bosch ; Sophie Janssens ; Vincent TimmermanSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-08-15.
Abstract
Missense mutations (K141N and K141E) in the -crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.
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DOI: 10.1093/hmg/ddq234
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Joy" uniqKey="Irobi J" first="Joy" last="Irobi">Joy Irobi</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Almeida Souza, Leonardo" sort="Almeida Souza, Leonardo" uniqKey="Almeida Souza L" first="Leonardo" last="Almeida-Souza">Leonardo Almeida-Souza</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Asselbergh, Bob" sort="Asselbergh, Bob" uniqKey="Asselbergh B" first="Bob" last="Asselbergh">Bob Asselbergh</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="De Winter, Vicky" sort="De Winter, Vicky" uniqKey="De Winter V" first="Vicky" last="De Winter">Vicky De Winter</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Goethals, Sofie" sort="Goethals, Sofie" uniqKey="Goethals S" first="Sofie" last="Goethals">Sofie Goethals</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Dierick, Ines" sort="Dierick, Ines" uniqKey="Dierick I" first="Ines" last="Dierick">Ines Dierick</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Krishnan, Jyothsna" sort="Krishnan, Jyothsna" uniqKey="Krishnan J" first="Jyothsna" last="Krishnan">Jyothsna Krishnan</name><affiliation><mods:affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Timmermans, Jean Pierre" sort="Timmermans, Jean Pierre" uniqKey="Timmermans J" first="Jean-Pierre" last="Timmermans">Jean-Pierre Timmermans</name><affiliation><mods:affiliation>Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium and</mods:affiliation></affiliation></author><author><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><affiliation><mods:affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="De Jonghe, Peter" sort="De Jonghe, Peter" uniqKey="De Jonghe P" first="Peter" last="De Jonghe">Peter De Jonghe</name><affiliation><mods:affiliation>Neurogenetics Groups, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology, University Hospital of Antwerp, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Van Den Bosch, Ludo" sort="Van Den Bosch, Ludo" uniqKey="Van Den Bosch L" first="Ludo" last="Van Den Bosch">Ludo Van Den Bosch</name><affiliation><mods:affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Janssens, Sophie" sort="Janssens, Sophie" uniqKey="Janssens S" first="Sophie" last="Janssens">Sophie Janssens</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation></author><author><name sortKey="Timmerman, Vincent" sort="Timmerman, Vincent" uniqKey="Timmerman V" first="Vincent" last="Timmerman">Vincent Timmerman</name><affiliation><mods:affiliation>Peripheral Neuropathy and</mods:affiliation></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: vincent.timmerman@molgen.vib-ua.be</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="2010-08-15">2010-08-15</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">16</biblScope><biblScope unit="page" from="3254">3254</biblScope><biblScope unit="page" to="3265">3265</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">FEA6C2208980AF366288EAA072FFA94CB78C6DA0</idno><idno type="DOI">10.1093/hmg/ddq234</idno><idno type="ArticleID">ddq234</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">Missense mutations (K141N and K141E) in the -crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Joy Irobi</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Leonardo Almeida-Souza</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Bob Asselbergh</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Vicky De Winter</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Sofie Goethals</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Ines Dierick</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Jyothsna Krishnan</name><affiliations><json:string>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</json:string></affiliations></json:item><json:item><name>Jean-Pierre Timmermans</name><affiliations><json:string>Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium and</json:string></affiliations></json:item><json:item><name>Wim Robberecht</name><affiliations><json:string>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</json:string></affiliations></json:item><json:item><name>Peter De Jonghe</name><affiliations><json:string>Neurogenetics Groups, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium,</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string><json:string>Division of Neurology, University Hospital of Antwerp, Belgium</json:string></affiliations></json:item><json:item><name>Ludo Van Den Bosch</name><affiliations><json:string>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</json:string></affiliations></json:item><json:item><name>Sophie Janssens</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string></affiliations></json:item><json:item><name>Vincent Timmerman</name><affiliations><json:string>Peripheral Neuropathy and</json:string><json:string>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</json:string><json:string>E-mail: vincent.timmerman@molgen.vib-ua.be</json:string></affiliations></json:item></author><articleId><json:string>ddq234</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Missense mutations (K141N and K141E) in the -crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. 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and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation></author><author xml:id="author-4"><persName><forename type="first">Vicky</forename><surname>De Winter</surname></persName><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation></author><author xml:id="author-5"><persName><forename type="first">Sofie</forename><surname>Goethals</surname></persName><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation></author><author xml:id="author-6"><persName><forename type="first">Ines</forename><surname>Dierick</surname></persName><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation></author><author xml:id="author-7"><persName><forename type="first">Jyothsna</forename><surname>Krishnan</surname></persName><affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</affiliation></author><author xml:id="author-8"><persName><forename type="first">Jean-Pierre</forename><surname>Timmermans</surname></persName><affiliation>Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium and</affiliation></author><author xml:id="author-9"><persName><forename type="first">Wim</forename><surname>Robberecht</surname></persName><affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</affiliation></author><author xml:id="author-10"><persName><forename type="first">Peter</forename><surname>De Jonghe</surname></persName><affiliation>Neurogenetics Groups, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium,</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation><affiliation>Division of Neurology, University Hospital of Antwerp, Belgium</affiliation></author><author xml:id="author-11"><persName><forename type="first">Ludo</forename><surname>Van Den Bosch</surname></persName><affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</affiliation></author><author xml:id="author-12"><persName><forename type="first">Sophie</forename><surname>Janssens</surname></persName><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation></author><author xml:id="author-13"><persName><forename type="first">Vincent</forename><surname>Timmerman</surname></persName><email>vincent.timmerman@molgen.vib-ua.be</email><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</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="2010-08-15"></date><biblScope unit="volume">19</biblScope><biblScope unit="issue">16</biblScope><biblScope unit="page" from="3254">3254</biblScope><biblScope unit="page" to="3265">3265</biblScope></imprint></monogr><idno type="istex">FEA6C2208980AF366288EAA072FFA94CB78C6DA0</idno><idno type="DOI">10.1093/hmg/ddq234</idno><idno type="ArticleID">ddq234</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-06-10</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Missense mutations (K141N and K141E) in the -crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.</p></abstract></profileDesc><revisionDesc><change when="2010-06-10">Created</change><change when="2010-08-15">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/FEA6C2208980AF366288EAA072FFA94CB78C6DA0/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/ddq234</article-id><article-id pub-id-type="publisher-id">ddq234</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Mutant HSPB8 causes motor neuron-specific neurite degeneration</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Irobi</surname><given-names>Joy</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Almeida-Souza</surname><given-names>Leonardo</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Asselbergh</surname><given-names>Bob</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>De Winter</surname><given-names>Vicky</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Goethals</surname><given-names>Sofie</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Dierick</surname><given-names>Ines</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Krishnan</surname><given-names>Jyothsna</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Timmermans</surname><given-names>Jean-Pierre</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Robberecht</surname><given-names>Wim</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>De Jonghe</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Van Den Bosch</surname><given-names>Ludo</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Janssens</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Timmerman</surname><given-names>Vincent</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af3">3</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Peripheral Neuropathy and</addr-line></aff><aff id="af2"><label>2</label><addr-line>Neurogenetics Groups, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium</addr-line>,</aff><aff id="af3"><label>3</label><addr-line>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium</addr-line>,</aff><aff id="af4"><label>4</label><addr-line>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium</addr-line>,</aff><aff id="af5"><label>5</label><addr-line>Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium</addr-line> and</aff><aff id="af6"><label>6</label><addr-line>Division of Neurology, University Hospital of Antwerp</addr-line>, <country>Belgium</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>VIB, Department of Molecular Genetics</addr-line>, <institution>University of Antwerp—CDE</institution>, <addr-line>Universiteitsplein 1, Building V, 2610 Antwerpen</addr-line>, <country>Belgium</country>. Tel: <phone>+32 32651024</phone>; Fax: <fax>+32 32651012</fax>; Email: <email>vincent.timmerman@molgen.vib-ua.be</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>8</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>10</day><month>6</month><year>2010</year></pub-date><volume>19</volume><issue>16</issue><fpage>3254</fpage><lpage>3265</lpage><history><date date-type="received"><day>5</day><month>4</month><year>2010</year></date><date date-type="accepted"><day>6</day><month>6</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><abstract><p>Missense mutations (K141N and K141E) in the &agr;-crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Mutant HSPB8 causes motor neuron-specific neurite degeneration</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Mutant HSPB8 causes motor neuron-specific neurite degeneration</title></titleInfo><name type="personal"><namePart type="given">Joy</namePart><namePart type="family">Irobi</namePart><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Leonardo</namePart><namePart 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type="family">Timmermans</namePart><affiliation>Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wim</namePart><namePart type="family">Robberecht</namePart><affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">De Jonghe</namePart><affiliation>Neurogenetics Groups, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium,</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation><affiliation>Division of Neurology, University Hospital of Antwerp, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ludo</namePart><namePart type="family">Van Den Bosch</namePart><affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sophie</namePart><namePart type="family">Janssens</namePart><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vincent</namePart><namePart type="family">Timmerman</namePart><affiliation>Peripheral Neuropathy and</affiliation><affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</affiliation><affiliation>E-mail: vincent.timmerman@molgen.vib-ua.be</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">2010-08-15</dateIssued><dateCreated encoding="w3cdtf">2010-06-10</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>Missense mutations (K141N and K141E) in the -crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. 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