The dystonia-associated protein torsina modulates synaptic vesicle recycling. Export

@article{citeulike:2192066, abstract = {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 and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild-type (wt) and mutant torsinA. Snapin co-localised with endogenous torsinA on dense core granules in PC12 cells and is recruited to perinuclear inclusions containing mutant E-torsinA in neuroblastoma SH-SY5Y cells. In view of these observations, synaptic vesicle recycling was analysed using the lipophilic dye FM1-43 and an antibody directed against an intravesicular epitope of synaptotagmin I. We found that over-expression of wt-torsinA negatively affects synaptic vesicle endocytosis. Conversely, over-expression of E-torsinA in neuroblastoma cells increases FM1-43 uptake. Knock down of snapin and/or torsinA using siRNAs 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 over-expression of 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.}, address = {Department of Clinical Neurosciences, Royal Free and University College Medical School, London NW3 2PF.}, author = {Granata, Alessandra and Watson, Rose and Collinson, Lucy M M. and Schiavo, Giampietro and Warner, Thomas T T.}, citeulike-article-id = {2192066}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M704097200}, citeulike-linkout-1 = {http://www.jbc.org/cgi/content/abstract/283/12/7568}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18167355}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18167355}, day = {31}, doi = {10.1074/jbc.M704097200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {aaa-atpase}, month = {December}, posted-at = {2008-03-20 18:03:19}, priority = {2}, title = {The dystonia-associated protein torsina modulates synaptic vesicle recycling.}, url = {http://dx.doi.org/10.1074/jbc.M704097200}, year = {2007} }

TY - JOUR ID - citeulike:2192066 L3 - citeulike-article-id:2192066 N2 - 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 and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild-type (wt) and mutant torsinA. Snapin co-localised with endogenous torsinA on dense core granules in PC12 cells and is recruited to perinuclear inclusions containing mutant E-torsinA in neuroblastoma SH-SY5Y cells. In view of these observations, synaptic vesicle recycling was analysed using the lipophilic dye FM1-43 and an antibody directed against an intravesicular epitope of synaptotagmin I. We found that over-expression of wt-torsinA negatively affects synaptic vesicle endocytosis. Conversely, over-expression of E-torsinA in neuroblastoma cells increases FM1-43 uptake. Knock down of snapin and/or torsinA using siRNAs 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 over-expression of 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. JF - J Biol Chem SN - 0021-9258 AD - Department of Clinical Neurosciences, Royal Free and University College Medical School, London NW3 2PF. TI - The dystonia-associated protein torsina modulates synaptic vesicle recycling. KW - aaa-atpase AU - Granata, Alessandra AU - Watson, Rose AU - Collinson, Lucy M AU - Schiavo, Giampietro AU - Warner, Thomas T PY - 2007/12/31/ UR - http://dx.doi.org/10.1074/jbc.M704097200 ER -