Severing saves microtubules

杨柳

Mutations in Spastin are associated with Hereditary Spastic Paraplegia (HSP), a disease characterized by retrograde axonal degeneration and a spastic gait. On page 599, Evans et al. demonstrate that Spastin is a microtubule-severing protein. The result leaves an unresolved paradox: how can the loss of a microtubule-severing protein result in shorter microtubule fibers?
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Spastin is a member of the AAA ATPase protein family, and thus has a highly conserved ATP-binding domain. Within the family, Spastin is most like Katanin, a microtubule-severing protein required for the function of worm meiosis and rodent neurons. Spastin overexpression decreases the number of microtubules in cells, suggesting that it too might cut microtubules.! M' J$ @9 l) P+ ^6 |( l

6 A. D: b' a. Y2 }' Z2 zThe team generated point mutations that disrupted ATP binding or hydrolysis. ATP binding was required for Spastin association with microtubules, ATP hydrolysis was necessary for microtubule release, and addition of recombinant Spastin severed microtubules in permeabilized cells and in vitro. Disease-associated mutations were found to lack either ATPase activity or severing activity, suggesting that they induce axonal degeneration by failing to cut microtubules fibers.
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Why cleavage failure results in degeneration of long central nervous system axons in HSP remains obscure. The team is currently testing whether internal cleavage of microtubules by Spastin is important for branching or redirection of already established fibers. They are also trying to determine how Katanin and Spastin activities differ in neurons.(A spastin mutant (green) that binds to, )