A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition
Identifieur interne : 001320 ( Istex/Corpus ); précédent : 001319; suivant : 001321A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition
Auteurs : Anne Tarrade ; Coralie Fassier ; Sabrina Courageot ; Delphine Charvin ; Jrmie Vitte ; Leticia Peris ; Alain Thorel ; Etienne Mouisel ; Nuria Fonknechten ; Natacha Roblot ; Danielle Seilhean ; Andre Dirich ; Jean Jacques Hauw ; Judith MelkiSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2006-12-15.
Abstract
Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated -tubulin and dynamic microtubules composed almost exclusively of tyrosinated -tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.
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DOI: 10.1093/hmg/ddl431
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<front><div type="abstract">Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated -tubulin and dynamic microtubules composed almost exclusively of tyrosinated -tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.</div>
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<affiliation>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</affiliation>
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<affiliation>Universities of Evry and Paris XI, Evry F-91025, France,</affiliation>
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<surname>Charvin</surname>
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<note type="biography">Present address: Institute of Neurosciences, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fdrale de Lausanne, CH-1015 Lausanne, Switzerland.</note>
<affiliation>Present address: Institute of Neurosciences, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fdrale de Lausanne, CH-1015 Lausanne, Switzerland.</affiliation>
<affiliation>Molecular Neurogenetics Laboratory, INSERM, U798, Evry F-91057, France,</affiliation>
<affiliation>Universities of Evry and Paris XI, Evry F-91025, France,</affiliation>
</author>
<author xml:id="author-5"><persName><forename type="first">Jrmie</forename>
<surname>Vitte</surname>
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<affiliation>Molecular Neurogenetics Laboratory, INSERM, U798, Evry F-91057, France,</affiliation>
<affiliation>Universities of Evry and Paris XI, Evry F-91025, France,</affiliation>
</author>
<author xml:id="author-6"><persName><forename type="first">Leticia</forename>
<surname>Peris</surname>
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<affiliation>INSERM Unit 366-DRDC/CS CEA, Grenoble, France,</affiliation>
</author>
<author xml:id="author-7"><persName><forename type="first">Alain</forename>
<surname>Thorel</surname>
</persName>
<affiliation>Centre des Matriaux, Ecole des Mines de Paris and CNRS UMR 7633, Evry, France,</affiliation>
</author>
<author xml:id="author-8"><persName><forename type="first">Etienne</forename>
<surname>Mouisel</surname>
</persName>
<affiliation>Molecular Neurogenetics Laboratory, INSERM, U798, Evry F-91057, France,</affiliation>
<affiliation>Universities of Evry and Paris XI, Evry F-91025, France,</affiliation>
</author>
<author xml:id="author-9"><persName><forename type="first">Nuria</forename>
<surname>Fonknechten</surname>
</persName>
<affiliation>Genoscope, Centre National de Squenage and CNRS UMR 8030, Evry, France,</affiliation>
</author>
<author xml:id="author-10"><persName><forename type="first">Natacha</forename>
<surname>Roblot</surname>
</persName>
<affiliation>Molecular Neurogenetics Laboratory, INSERM, U798, Evry F-91057, France,</affiliation>
<affiliation>Universities of Evry and Paris XI, Evry F-91025, France,</affiliation>
</author>
<author xml:id="author-11"><persName><forename type="first">Danielle</forename>
<surname>Seilhean</surname>
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<author xml:id="author-12"><persName><forename type="first">Andre</forename>
<surname>Dirich</surname>
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<author xml:id="author-13"><persName><forename type="first">Jean Jacques</forename>
<surname>Hauw</surname>
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<surname>Melki</surname>
</persName>
<email>j.melki@genopole.inserm.fr</email>
<affiliation>Molecular Neurogenetics Laboratory, INSERM, U798, Evry F-91057, France,</affiliation>
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<abstract><p>Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated -tubulin and dynamic microtubules composed almost exclusively of tyrosinated -tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.</p>
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<title-group><article-title>A mutation of <italic>spastin</italic>
is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Tarrade</surname>
<given-names>Anne</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="author-notes" rid="FN1">†</xref>
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<contrib contrib-type="author"><name><surname>Fassier</surname>
<given-names>Coralie</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="author-notes" rid="FN1">†</xref>
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<contrib contrib-type="author"><name><surname>Courageot</surname>
<given-names>Sabrina</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Charvin</surname>
<given-names>Delphine</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="author-notes" rid="FN2">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vitte</surname>
<given-names>Jérémie</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peris</surname>
<given-names>Leticia</given-names>
</name>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Thorel</surname>
<given-names>Alain</given-names>
</name>
<xref ref-type="aff" rid="af4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mouisel</surname>
<given-names>Etienne</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fonknechten</surname>
<given-names>Nuria</given-names>
</name>
<xref ref-type="aff" rid="af5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Roblot</surname>
<given-names>Natacha</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Seilhean</surname>
<given-names>Danielle</given-names>
</name>
<xref ref-type="aff" rid="af6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Diérich</surname>
<given-names>Andrée</given-names>
</name>
<xref ref-type="aff" rid="af7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hauw</surname>
<given-names>Jean Jacques</given-names>
</name>
<xref ref-type="aff" rid="af6">6</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Melki</surname>
<given-names>Judith</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af2">2</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
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<aff id="af1"><label>1</label>
<addr-line>Molecular Neurogenetics Laboratory</addr-line>
, <institution>INSERM</institution>
, <addr-line>U798, Evry F-91057</addr-line>
, <country>France</country>
,</aff>
<aff id="af2"><label>2</label>
<institution>Universities of Evry and Paris XI</institution>
, <addr-line>Evry F-91025</addr-line>
, <country>France</country>
,</aff>
<aff id="af3"><label>3</label>
<institution>INSERM Unité 366-DRDC/CS CEA</institution>
, <addr-line>Grenoble</addr-line>
, <country>France</country>
,</aff>
<aff id="af4"><label>4</label>
<addr-line>Centre des Matériaux</addr-line>
, <institution>Ecole des Mines de Paris and CNRS</institution>
<addr-line>UMR 7633, Evry</addr-line>
, <country>France</country>
,</aff>
<aff id="af5"><label>5</label>
<addr-line>Genoscope</addr-line>
, <institution>Centre National de Séquençage and CNRS UMR 8030</institution>
, <addr-line>Evry</addr-line>
, <country>France</country>
,</aff>
<aff id="af6"><label>6</label>
<addr-line>Assistance Publique Hôpitaux de Paris, Laboratoire de Neuropathologie Raymond Escourolle</addr-line>
, <institution>Groupe Hospitalier Pitié-Salpétrière and Paris VI University</institution>
, <country>France</country>
and</aff>
<aff id="af7"><label>7</label>
<addr-line>Institut de Génétique et de Biologie Moléculaire et Cellulaire</addr-line>
, <institution>INSERM</institution>
, <addr-line>CNRS, ULP, Illkirch</addr-line>
, <country>France</country>
</aff>
<author-notes><corresp id="cor1"><label>*</label>
To whom the correspondence should be addressed at: <addr-line>Molecular Neurogenetics Laboratory, INSERM</addr-line>
, <institution>University of Evry</institution>
, <addr-line>U-798, 2 rue Gaston Crémieux, CP5724, 91057 Evry</addr-line>
, <country>France</country>
. Tel: <phone>+33 160874552</phone>
; Fax: <fax>+33 160874550</fax>
; Email: <email>j.melki@genopole.inserm.fr</email>
</corresp>
<fn id="FN1" symbol="†"><p>The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.</p>
</fn>
<fn id="FN2" symbol="‡"><p>Present address: Institute of Neurosciences, Swiss Federal Institute of Technology Lausanne, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>December</month>
<year>2006</year>
</pub-date>
<pub-date pub-type="epub"><day>13</day>
<month>11</month>
<year>2006</year>
</pub-date>
<volume>15</volume>
<issue>24</issue>
<fpage>3544</fpage>
<lpage>3558</lpage>
<history><date date-type="received"><day>20</day>
<month>9</month>
<year>2006</year>
</date>
<date date-type="accepted"><day>1</day>
<month>11</month>
<year>2006</year>
</date>
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<copyright-statement>© 2006 The Author(s)</copyright-statement>
<copyright-year>2006</copyright-year>
<license license-type="open-access" 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>Mutations of the <italic>spastin</italic>
gene (<italic>Sp</italic>
) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse <italic>Sp</italic>
gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated α-tubulin and dynamic microtubules composed almost exclusively of tyrosinated α-tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both <italic>in vivo</italic>
and <italic>in vitro</italic>
. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.</p>
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