Abstract
SUMMARYMutations 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.
Highlights
Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurological disorders, mainly characterized by a bilateral and slowly progressive spasticity of the lower limbs caused by the degeneration of the corticospinal tracts (Reid, 2003; Fink, 2006)
Very low concentrations of microtubule-targeting drugs substantially rescue the axon phenotype associated with loss of spastin function in mammalian cortical neurons, thereby indicating that alterations in microtubule dynamics are a primary cause of the mouse mutant phenotype
Using primary cultures of cortical neurons from spastinmutant mice, we have shown that these axonal swellings occur in a specialized region of the axon characterized by an abrupt transition between stable and dynamic microtubules, which suggests that alterations in microtubule dynamics primarily give rise to this mutant phenotype (Tarrade et al, 2006)
Summary
Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurological disorders, mainly characterized by a bilateral and slowly progressive spasticity of the lower limbs caused by the degeneration of the corticospinal tracts (Reid, 2003; Fink, 2006). Mutations in the SPG4 gene encoding spastin, a member of the AAA (ATPase associated with diverse cellular activities) superfamily, are responsible for the most frequent form of autosomal dominant HSP (Hazan et al, 1999). (Errico et al, 2002; Du et al, 2010; Solowska et al, 2010), the vast majority of SPG4 mutations, which affect the ATPase domain, are thought to cause this form of HSP by haploinsufficiency (Fonknechten et al, 2000; Charvin et al, 2003; Roll-Mecak and Vale, 2008; Riano et al, 2009).
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