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Human Molecular Genetics Advance Access published online on November 13, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl431
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© 2006 The Author(s)
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.

A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition

Anne Tarrade1,2, Coralie Fassier1,2, Sabrina Courageot1,2, Delphine Charvin1,2, Jérémie Vitte1,2, Leticia Peris3, Alain Thorel4, Etienne Mouisel1,2, Nuria Fonknechten5, Natacha Roblot1,2, Danielle Seilhean6, Andrée Diérich7, Jean Jacques Hauw6 and Judith Melki1,2,*

1 Molecular Neurogenetics Laboratory, Inserm, University of Evry, U798,2 rue Gaston Crémieux, CP5724, Evry, F-91057 France 2 Evry and Paris XI Universities, Evry, France 3 Inserm Unité 366-DRDC/CS CEA, Grenoble, France 4 Centre des Matériaux, Ecole des Mines de Paris and CNRS UMR 7633, Evry, France 5 Genoscope, Centre National de Séquençage and CNRS UMR 8030, Evry, France 6 Assistance Publique Hôpitaux de Paris, Laboratoire de Neuropathologie Raymond Escourolle, Groupe Hospitalier Pitié-Salpétrière and Paris VI University, France 7 Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, CNRS, ULP, Illkirch, France

* j.melki{at}genopole.inserm.fr

Received September 20, 2006; Revised November 1, 2006; Accepted November 1, 2006

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 {alpha}-tubulin, and dynamic microtubules composed almost exclusively of tyrosinated {alpha}-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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