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J. Biol. Chem., Vol. 283, Issue 12, 7568-7579, March 21, 2008

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The Dystonia-associated Protein TorsinA Modulates Synaptic Vesicle Recycling^*

Alessandra Granata, Rose Watson, Lucy M. Collinson, Giampietro Schiavo¹, and Thomas T. Warner²

From the Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom and the Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom

The loss of a glutamic acid residue in the AAA-ATPase (ATPases associated with diverse cellular activities) torsinA is responsible for most cases of early onset autosomal dominant primary dystonia. In this study, we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. Snapin co-localized with endogenous torsinA on dense core granules in PC12 cells and was recruited to perinuclear inclusions containing mutant E-torsinA in neuroblastoma SH-SY5Y cells. In view of these observations, synaptic vesicle recycling was analyzed using the lipophilic dye FM1-43 and an antibody directed against an intravesicular epitope of synaptotagmin I. We found that overexpression of wild type torsinA negatively affects synaptic vesicle endocytosis. Conversely, overexpression of E-torsinA in neuroblastoma cells increases FM1-43 uptake. Knockdown of snapin and/or torsinA using small interfering RNAs had a similar inhibitory effect on the exo-endocytic process. In addition, down-regulation of torsinA causes the persistence of synaptotagmin I on the plasma membrane, which closely resembles the effect observed by the overexpression of the E-torsinA mutant. Altogether, these findings suggest that torsinA plays a role together with snapin in regulated exocytosis and that E-torsinA exerts its pathological effects through a loss of function mechanism. This may affect neuronal uptake of neurotransmitters, such as dopamine, playing a role in the development of dystonic movements.

Received for publication, May 17, 2007 , and in revised form, December 24, 2007.

^* This work was supported by a grant from the Wellcome Trust (to A. G.), Cancer Research UK (to L. M. C. and G. S), and the Bachmann-Strauss Dystonia and Parkinson Foundation (to T.T.W.). 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.

The on-line version of this article (available at http://www.jbcorg) contains supplemental Figs. S1-S7.

¹ To whom correspondence may be addressed. Tel.: 44-20-7269-3300; Fax: 44-20-7269-3417; E-mail: giampietro.schiavo{at}cancer.org.uk. ² To whom correspondence may be addressed: Tel.: 44-20-7830-2951; Fax: 44-20-7472-6829; E-mail: t.warner{at}medsch.ucl.ac.uk.

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