A new role for spastin

September 1, 2004

Nature Reviews Neuroscience 5, 673 (2004); doi:10.1038/nrn1501

<http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrn/journal/v5/n9/full/nrn1501\

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NEUROLOGICAL DISORDERS

A new role for spastin

Jane Qiu

Hereditary spastic paraplegia is a devastating motor disorder that causes

spastic weakness of the lower limbs and eventual axonal degeneration. More than

40% of all cases are associated with mutations in one gene, spastin, but little

is known about how such mutations cause the disease. Reporting in Current

Biology, Trotta et al. found that spastin mutations might lead to defects in

neurotransmission by affecting microtubule functions.

Confocal micrograph of a Drosophila melanogaster neuromuscular junction.

Signals represent immunoreactivity for different antibodies. Red,

anti-horseradish peroxidase labelling neuronal membranes; green, anti-D-spastin;

blue, anti-acetylated tubulin, which detects stable and long-lived microtubule

filaments. Note that regions where D-spastin is enriched also appear to be

regions where stable microtubules are excluded. Image courtesy of K. Broadie,

Vanderbilt University, USA.

Spastin is an ATPase that contains a microtubule-interacting domain. Therefore,

the authors asked whether microtubule structure or function might be affected by

abnormal spastin expression. They studied this in the Drosophila melanogaster

neuromuscular junction (NMJ) synapse, which has been widely used to assay

functions of the microtubule cytoskeleton and to model its role in inherited

neurological diseases.

Spastin is expressed at high levels in the nervous system of both mammals and D.

melanogaster, but its subcellular localization has not been characterised.

Trotta et al. found that the protein is highly enriched in axons and synaptic

connections. They showed that spastin co-localizes with a synaptic vesicle

protein, synaptotagmin, indicating that spastin is expressed in the synaptic

vesicle pool domain of the presynaptic bouton.

The authors showed that knockdown of ubiquitous spastin expression by RNA

interference causes lethality. When they knocked down spastin expression

specifically in the nervous system, the animals had very poor coordination and

locomotor abilities. Interestingly, overexpression of spastin, either

ubiquitously or specifically in the nervous system, was also lethal to embryos

or early larvae. The authors suggest that a correct dose of spastin expression

is crucial for normal development.

Spastin interacts with microtubules and prevents their assembly in vitro. The

authors assessed the effects of altered spastin expression in vivo on

microtubule assembly and synaptic transmission. They found that, at the NMJ

presynaptic terminal, spastin knockdown in the neuron led to an accumulation of

acetylated -tubulin, the post-translationally modified form of tubulin that

occurs only in structurally stable microtubules. Conversely, neuron-specific

overexpression of spastin caused a reduction in stabilized tubulin and, often,

the stabilized tubulin network was no longer detectable.

The authors showed that these effects on microtubule assembly correlated with

changes in synaptic transmission. When they stimulated the motor nerve and

measured glutamate-gated synaptic currents in the voltage-clamped muscle, they

found that loss of spastin expression resulted in an increase in current

amplitude, whereas spastin overexpression had the opposite effect. These effects

could be reversed by pharmacological agents that affect microtubule stability.

Normal functions were restored in spastin knockdown flies by nocodazole, which

disassembles microtubules, and in flies overexpressing spastin by taxol, which

stabilizes tubulin monomers. In both cases synaptic transmission was

indistinguishable from that in normal animals.

The study shows that spastin is enriched at the synapse and controls synaptic

transmission by regulating microtubule assembly. Trotta et al. conclude that it

is likely that defects in microtubule stability are the primary cause of

hereditary spastic paraplegia. This mechanistic insight has significant

implications in designing therapeutic strategies to treat the illness.

References and links

ORIGINAL RESEARCH PAPER

Trotta, N. et al. The hereditary spastic paraplegia gene, spastin,

regulates microtubule stability to modulate synaptic structure and function.

Curr. Biol. 14, 1135-1147 (2004) |

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