The hereditary spastic paraplegias (HSP) are a collection of neurodegenerative disorders characterised by progressive weakness and spasticity of the legs. They are caused by developmental failure or degeneration of motor axons, or nerve fibres, in the corticospinal tract, and are an important cause of permanent disability. Around 40% of autosomal dominant cases of HSP are caused by mutations in the SPAST gene. HSP cases show highly variable age of onset and severity, both between and within families, and haploinsufficiency for SPAST is the likely mechanism in most cases.

Current treatments to provide symptomatic relief for HSP include muscle relaxants to relieve spasticity, and physical therapy to maintain muscle strength and range of movement. However, these treatments do not alter or slow the disease, and the development of effective therapies has been hampered by a lack of knowledge regarding the molecular mechanisms underlying axonal degeneration.

Previous work has shown that spastin, the SPAST gene product, shares homology with the p60 subunit of katanin, and both proteins have been shown to be ATP-dependent microtubule-severing proteins. Microtubules, components of the cell’s cytoskeleton, are fundamentally important for the correct outgrowth of axons, but how microtubule-severing activities might relate to axonal degeneration in HSP is unclear. This study uses confocal time-lapse imaging in the zebrafish embryonic CNS to demonstrate that both spastin and katanin are required in axons for the formation of forward-moving dynamic microtubules, and also at the growth cone, the specialised guidance structure at the axon’s growing tip. The effects of lowering the levels of spastin and katanin, mimicking haploinsufficiency, were monitored in embryonic neurons using a fluorescent protein as a marker for the growing microtubules. Reduced expression of either spastin or katanin severely impaired formation of dynamic microtubules and inhibited outgrowth of axons and growth cone motility. The microtubule-destabilising drug nocodazole also abolished microtubule dynamics, suppressed growth cone motility and enhanced the severity of the phenotypes caused by reduced spastin expression in the embryos.

These results reveal crucial functions for microtubule-severing proteins in neuronal development, through their roles in dynamic microtubule formation, axonal outgrowth and growth cone protrusive activity. SPAST mutations might cause depletion of the pool of dynamic microtubules in neurons, leading to a failure to maintain long axons and the axonal transport machinery within, which could explain the distal axonopathies that are observed in HSP patients. Future studies will aim to identify compounds that modulate microtubule dynamics, which might be of therapeutic value for treatment of HSP.