Mice with HSP used in study

Drugs known to stabilise microtubule dynamics had a positive effect on impaired nerve cells in mice with SPG4 HSP in this French study.


Mice with SPG4 type HSP develop progressive degeneration of the long arms (axons) of spinal cord nerve cells (neurons), characterized by both physical changes in cell microtubules and impaired transport function, similar to what is found in studies of SPG4 HSP in humans.



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 here 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.


Altogether, 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.


SOURCE: Dis Model Mech. 2012 Jul 5. [Epub ahead of print]  PMID: 22773755 [PubMed – as supplied by publisher]


Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knock-out mice.


Fassier C, Tarrade A, Peris L, Courageot S, Mailly P, Dalard C, Delga S, Roblot N, Lefevre J, Job D, Hazan J, Curmi PA, Melki J.


UMR CNRS 7224 / Inserm U952 / Université P. & M. Curie, Paris, France;


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