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Human Molecular Genetics Advance Access originally published online on December 8, 2005
Human Molecular Genetics 2006 15(2):307-318; doi:10.1093/hmg/ddi447
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners

Christopher M. Sanderson1,{dagger}, James W. Connell2,{dagger}, Thomas L. Edwards2, Nicholas A. Bright3, Simon Duley4, Amanda Thompson4, J. Paul Luzio3 and Evan Reid2,*

1The Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool L69 3BX, UK, 2Department of Medical Genetics and 3Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK and 4Medical Research Council Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge CB10 1SB, UK

* To whom correspondence should be addressed at: Addenbrooke's Hospital, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 2XY, UK. Tel: +44 1223762632; Fax: +44 1223762640; Email: ealr4{at}cam.ac.uk

Received June 6, 2005; Revised November 23, 2005; Accepted December 1, 2005

The pure hereditary spastic paraplegias (HSPs) are a group of conditions in which there is a progressive length-dependent degeneration of the distal ends of the corticospinal tract axons, resulting in spastic paralysis of the legs. Pure HSPs are most frequently inherited in an autosomal-dominant pattern and are commonly caused by mutations either in the SPG4 gene spastin or in the SPG3A gene atlastin. To identify binding partners for spastin, we carried out a yeast two-hybrid screen on a brain cDNA library, using spastin as bait. Remarkably, nearly all of the positive interacting prey clones coded for atlastin. We have verified the physiological relevance of this interaction using co-immunoprecipitation, glutathione S-transferase pull-down and intracellular co-localization experiments. We show that the spastin domain required for binding to atlastin lies within the N-terminal 80 residues of the protein, a region that is only present in the predominantly cytoplasmic, full-length spastin isoform. These data suggest that spastin and atlastin function in the same biochemical pathway and that it is the cytoplasmic function of spastin which is important for the pathogenesis of HSP. They also provide further evidence for a physiological and pathological role of spastin in membrane dynamics.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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