Abstract
The hereditary spastic paraplegias (HSPs) are genetic conditions in which there is progressive axonal degeneration in the corticospinal tract. Autosomal dominant mutations, including nonsense, frameshift and missense changes, in the gene encoding the microtubule severing ATPase spastin are the most common cause of HSP in North America and northern Europe. In this study we report quantitative gait analysis using a motorized treadmill system, carried out on mice knocked-in for a disease-associated mutation affecting a critical residue in the Walker A motif of the spastin ATPase domain. At 4 months and at one year of age homozygous mutant mice had a number of abnormal gait parameters, including in stride length and stride duration, compared to heterozygous and wild-type littermates. Gait parameters in heterozygous animals did not differ from wild-type littermates. We conclude that quantitative gait analysis using the DigiGait system sensitively detects motor abnormalities in a hereditary spastic paraplegia model, and would be a useful method for analyzing the effects of pharmacological treatments for HSP.
Highlights
Hereditary spastic paraplegias (HSP) are genetically determined subtypes of motor neuron disease that are characterized by dying-back degeneration of the axons of the corticospinal tract [1,2,3,4,5]
Spastin protein was expressed in brain tissue from spastinwt/wt, spastinN384K/wt and spastinN384K/N384K animals (Fig 1C)
In light of the primary neuron axonal swelling phenotype observed in previous spastin mouse models, we examined whether similar swellings were present in primary neurons derived from spastinN384K/N384K mice
Summary
Hereditary spastic paraplegias (HSP) are genetically determined subtypes of motor neuron disease that are characterized by dying-back degeneration of the axons of the corticospinal tract [1,2,3,4,5]. In humans, they cause a progressive spastic gait abnormality that can begin from childhood to late adult life. Mutations in SPAST/SPG4, which encodes the microtubule severing ATPase spastin, are the most frequent cause of HSP [7]. In North America and northern Europe, mutations in this gene account for up to 40% of autosomal dominant uncomplicated HSP and around 10%
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