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Drosophila Spastin Regulates Synaptic Microtubule Networks and Is Required for Normal Motor Function

Sherwood, Nina Tang and Sun, Qi and Xue, Mingshan and Zhang, Bing and Zinn, Kai (2004) Drosophila Spastin Regulates Synaptic Microtubule Networks and Is Required for Normal Motor Function. PLoS Biology, 2 (12). pp. 2094-2111. ISSN 1544-9173. http://resolver.caltech.edu/CaltechAUTHORS:SHEpb04

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Abstract

The most common form of human autosomal dominant hereditary spastic paraplegia (AD-HSP) is caused by mutations in the SPG4 (spastin) gene, which encodes an AAA ATPase closely related in sequence to the microtubule-severing protein Katanin. Patients with AD-HSP exhibit degeneration of the distal regions of the longest axons in the spinal cord. Loss-of-function mutations in the Drosophila spastin gene produce larval neuromuscular junction (NMJ) phenotypes. NMJ synaptic boutons in spastin mutants are more numerous and more clustered than in wild-type, and transmitter release is impaired. spastin-null adult flies have severe movement defects. They do not fly or jump, they climb poorly, and they have short lifespans. spastin hypomorphs have weaker behavioral phenotypes. Overexpression of Spastin erases the muscle microtubule network. This gain-of-function phenotype is consistent with the hypothesis that Spastin has microtubule-severing activity, and implies that spastin loss-of-function mutants should have an increased number of microtubules. Surprisingly, however, we observed the opposite phenotype: in spastin-null mutants, there are fewer microtubule bundles within the NMJ, especially in its distal boutons. The Drosophila NMJ is a glutamatergic synapse that resembles excitatory synapses in the mammalian spinal cord, so the reduction of organized presynaptic microtubules that we observe in spastin mutants may be relevant to an understanding of human Spastin’s role in maintenance of axon terminals in the spinal cord.


Item Type:Article
Additional Information:Copyright: © 2004 Sherwood et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received April 20, 2004; Accepted October 12, 2004; Published November 30, 2004. We thank Elena Armand, Anna Salazar, Tambrea Ellison, Miguel Lemus, Nora Tu, and Darya Goloub for excellent help on various aspects of this project; Catalina Ruiz-Canada and Detlev Buttgereit for advice on tubulin staining; the Caltech Biological Imaging Center for use of confocal microscopes; David Mathog for generation of phylogenetic trees; Greg Macleod for discussions on electrophysiology; Renate Renkawitz-Pohl, Dan Woods, and Peter Bryant for antibodies; Anne Simon for WCS flies; Henri Bourbon for Rox8 advice and reagents; and David Sherwood and members of the Zinn and Zhang groups for helpful discussions. This work was supported by a National Institutes of Health RO1 grant to KZ and by an American Cancer Society postdoctoral fellowship to NTS. Most of the other driver-dependent lethal EP lines from the screen that produced T32 have been maintained in the Zinn lab, and this collection is available for distribution to other investigators. Conflicts of interest: The authors have declared that no conflicts of interest exist. Author contributions: NTS, QS, MX, BZ, and KZ conceived and designed the experiments. NTS, QS, and MX performed the experiments. NTS, QS, MX, and KZ analyzed the data. BZ oversaw the electrophysiology experiments and analysis. NTS and KZ wrote the paper.
Subject Keywords:aa, amino acid; AD-HSP, autosomal dominant hereditary spastic paraplegia; CNS, central nervous system; Dlg, Discs-large; EJP, excitatory junction potential; GS, GeneSwitch; LOF, loss of function; mAb, monoclonal antibody; mEJP, ‘‘mini’’ excitatory junction potential; NMJ, neuromuscular junction; QC, quantal content; sca, scabrous; spin, spinster; Syt, Synaptotagmin; VNC, ventral nerve cord; WCS, Canton S w-
Record Number:CaltechAUTHORS:SHEpb04
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:SHEpb04
Alternative URL:http://dx.doi.org/10.1371/journal.pbio.0020429
Official Citation:Sherwood NT, Sun Q, Xue M, Zhang B, Zinn K (2004) Drosophila Spastin regulates synaptic microtubule networks and is required for normal motor function. PLoS Biol 2(12): e429.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:303
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:18 May 2005
Last Modified:26 Dec 2012 08:39

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