Mutant HSPB8 causes motor neuron-specific neurite degeneration
Identifieur interne : 001202 ( Istex/Curation ); précédent : 001201; suivant : 001203Mutant 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 [Belgique] ; Ludo Van Den Bosch ; Sophie Janssens ; Vincent Timmerman [Belgique]Source :
- 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 Irobi<affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium and</mods:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation><affiliation><mods:affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Laboratory of Neurobiology and Experimental Neurology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation>Le document en format XML
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and</mods:affiliation><wicri:noCountry code="no comma">Peripheral Neuropathy and</wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="no comma">Peripheral Neuropathy and</wicri:noCountry></affiliation><affiliation><mods:affiliation>Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium,</mods:affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: vincent.timmerman@molgen.vib-ua.be</mods:affiliation><country wicri:rule="url">Belgique</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:FEA6C2208980AF366288EAA072FFA94CB78C6DA0</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/hmg/ddq234</idno><idno type="url">https://api.istex.fr/document/FEA6C2208980AF366288EAA072FFA94CB78C6DA0/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001226</idno><idno type="wicri:Area/Istex/Curation">001202</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Mutant HSPB8 causes motor neuron-specific neurite degeneration</title><author><name sortKey="Irobi, Joy" sort="Irobi, 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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField">and</wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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 wicri:level="1"><mods:affiliation>Division of Neurology, University Hospital of Antwerp, Belgium</mods:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Division of Neurology, University Hospital of Antwerp</wicri:regionArea></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><wicri:noCountry code="subField"></wicri:noCountry></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><wicri:noCountry code="subField"></wicri:noCountry></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 wicri:level="1"><mods:affiliation>E-mail: vincent.timmerman@molgen.vib-ua.be</mods:affiliation><country wicri:rule="url">Belgique</country></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></record>Pour manipuler ce document sous Unix (Dilib)
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