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Human Molecular Genetics Advance Access originally published online on January 18, 2008
Human Molecular Genetics 2008 17(9):1245-1252; doi:10.1093/hmg/ddn014
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity

Bettina Ebbing1,3,*, Klaudiusz Mann1, Agata Starosta1, Johann Jaud3, Ludger Schöls2, Rebecca Schüle2 and Günther Woehlke3,*

1 Institute for Cell Biology, University of Munich, Schillerstr. 42, D-80336 Munich, Germany 2 Hertie-Institute for Clinical Brain Research, Otfried-Müller-Str. 3, 72076 Tübingen, Germany 3 Physics Department E22, Technical University Munich, James-Franck-Str., 85747 Garching, Germany

* To whom correspondence should be addressed. Tel: +49 8928912486; Fax: +49 8928912523; Email: guenther.woehlke{at}lrz.uni-muenchen.de (G.W.); bettina.ebbing{at}lrz.uni-muenchen.de (B.E.)

Received October 30, 2007; Revised October 30, 2007; Accepted January 15, 2008

Hereditary spastic paraplegia (HSP) is a neurodegenerative disease caused by motoneuron degeneration. It is linked to at least 30 loci, among them SPG10, which causes dominant forms and originates in point mutations in the neuronal Kinesin-1 gene (KIF5A). Here, we investigate the motility of KIF5A and four HSP mutants. All mutations are single amino-acid exchanges and located in kinesin's motor or neck domain. The mutation in the neck (A361V) did not change the gliding properties in vitro, the others either reduced microtubule affinity or gliding velocity or both. In laser-trapping assays, none of the mutants moved more than a few steps along microtubules. Motility assays with mixtures of homodimeric wild-type, homodimeric mutant and heterodimeric wild-type/mutant motors revealed that only one mutant (N256S) reduces the gliding velocity at ratios present in heterozygous patients, whereas the others (K253N, R280C) do not. Attached to quantum dots as artificial cargo, mixtures involving N256S mutants produced slower cargo populations lagging behind in transport, whereas mixtures with the other mutants led to populations of quantum dots that rarely bound to microtubules. These differences indicate that the dominant inheritance of SPG10 is caused by two different mechanisms that both reduce the gross cargo flux, leading to deficient supply of the synapse.


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