title: Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice.
abstract: Mutations in SPG4, encoding the microtubule-severing protein spastin, are responsible for the most frequent form of hereditary spastic paraplegia (HSP), a heterogeneous group of genetic diseases characterized by degeneration of the corticospinal tracts. We previously reported that mice harboring a deletion in Spg4, generating a premature stop codon, develop progressive axonal degeneration characterized by focal axonal swellings associated with impaired axonal transport. To further characterize the molecular and cellular mechanisms underlying this mutant phenotype, we have assessed microtubule dynamics and axonal transport in primary cultures of cortical neurons from spastin-mutant mice. We show an early and marked impairment of microtubule dynamics all along the axons of spastin-deficient cortical neurons, which is likely to be responsible for the occurrence of axonal swellings and cargo stalling. Our analysis also reveals that a modulation of microtubule dynamics by microtubule-targeting drugs rescues the mutant phenotype of cortical neurons. Together, these results contribute to a better understanding of the pathogenesis of SPG4-linked HSP and ascertain the influence of microtubule-targeted drugs on the early axonal phenotype in a mouse model of the disease.
authors: Inserm U798, Laboratoire de Neurogénétique Moléculaire, Université d'Evry-Val d'Essonne et Paris XI, Evry, 91057, France. cfassier@snv.jussieu.fr
authors: Coralie
authors: C
authors: Fassier
authors: Anne
authors: A
authors: Tarrade
authors: Leticia
authors: L
authors: Peris
authors: Sabrina
authors: S
authors: Courageot
authors: Philippe
authors: P
authors: Mailly
authors: Cécile
authors: C
authors: Dalard
authors: Stéphanie
authors: S
authors: Delga
authors: Natacha
authors: N
authors: Roblot
authors: Julien
authors: J
authors: Lefèvre
authors: Didier
authors: D
authors: Job
authors: Jamilé
authors: J
authors: Hazan
authors: Patrick A
authors: PA
authors: Curmi
authors: Judith
authors: J
authors: Melki
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008959:Models, Neurological; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D015419:Spastic Paraplegia, Hereditary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000074181:Spastin; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D014747:Vinblastine; D000251:Adenosine Triphosphatases; D000074181:Spastin; C498515:Spast protein, mouse; D017239:Paclitaxel; D015739:Nocodazole