Both important for healthy cells
Study on zebrafish embryos shows both Spastin and Katanin are needed for normal cell microtubule growth and function. Symptoms are more severe when both are in short supply. Zebrafish embryos may provide a way to find and test potential drugs to treat HSP.
Mutations in the SPAST (SPG4) gene, which encodes the microtubule-severing protein Spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). Following on from previous work in our laboratory showing that spastin is required for axon outgrowth, we report here that the related microtubule-severing protein Katanin is also required for axon outgrowth in vivo.
Using confocal time-lapse imaging, we have identified requirements for spastin and katanin in maintaining normal axonal microtubule dynamics and growth cone motility in vivo, supporting a model in which microtubule severing is required for concerted growth of neuronal microtubules.
Simultaneous knockdown of spastin and katanin caused a more severe phenotype than did individual knockdown of either gene, suggesting that they have different but related functions in supporting axon outgrowth. In addition, the microtubule-destabilising drug nocodazole abolished microtubule dynamics and growth cone motility, and enhanced phenotypic severity in spast-knockdown zebrafish embryos.
Thus, disruption of microtubule dynamics might underlie neuronal dysfunction in this model, and this system could be used to identify compounds that modulate microtubule dynamics, some of which might have therapeutic potential in HSP.
Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia.
Butler R, Wood JD, Landers JA, Cunliffe VT.
MRC Centre for Developmental and Biomedical Genetics, Department of Biomedical Science, University of Sheffield, Sheffield, S10 2TN, UK.