Early onset dystonia is a movement disorder caused by loss of a glutamic acid residue (Glu302/303) in the carboxyl-terminal portion of the AAA+ protein, torsinA. We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wild-type torsinA and kinesin-I form a complex in vivo. In cultured cortical neurons, both proteins co-localized along processes with enrichment at growth cones. Wild-type torsinA expressed in CAD cells co-localized with endogenous KLC1 at the distal end of processes, whereas mutant torsinA remained confined to the cell body. Subcellular fractionation of adult rat brain revealed torsinA and KLC associated with cofractionating membranes, and both proteins were co-immunoprecipitated after cross-linking cytoplasmically oriented proteins on isolated rat brain membranes. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding.
Fellow of the Deutsche Forschungsgemeinschaft. Present address: Dept. of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.
This work was supported by research grants from the Dystonia Medical Research Foundation (to C. K. and P. I. H.), by the Jack Fasciana Fund for Support of Dystonia Research (X. O. B.), and by NINDS, National Institutes of Health, Grants NS28384 (to X. O. B.) and NS37409 (to X. O. B., V. R., and L. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
