The Dystonia-associated Protein TorsinA Modulates Synaptic Vesicle Recycling

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 (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 ΔE-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 ΔE-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 ΔE-torsinA mutant. Altogether, these findings suggest that torsinA plays a role together with snapin in regulated exocytosis and that ΔE-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. 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 ΔE-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 ΔE-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 ΔE-torsinA mutant. Altogether, these findings suggest that torsinA plays a role together with snapin in regulated exocytosis and that ΔE-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. The majority of cases of early onset, primary torsion dystonia are caused by a dominantly inherited mutation in the DYT1 (TOR1A) gene on chromosome 9q34 (1Ozelius L.J. Hewett J.W. Page C.E. Bressman S.B. Kramer P.L. Shalish C. de Leon D. Brin M.F. Raymond D. Corey D.P. Fahn S. Risch N.J. Buckler A.J. Gusella J.F. Breakefield X.O. Nat. Genet. 1997; 17: 40-48Crossref PubMed Scopus (900) Google Scholar). DYT1 dystonia manifests in childhood, typically with dystonia in a limb that spreads to the trunk and other limbs, usually sparing cranio-cervical muscles (2Fahn S. Bressman S.B. Marsden C.D. Adv. Neurol. 1998; 78: 1-10Crossref PubMed Google Scholar, 3Bressman S.B. de Leon D. Kramer P.L. Ozelius L.J. Brin M.F. Greene P.E. Fahn S. Breakefield X.O. Risch N.J. Ann. Neurol. 1994; 36: 771-777Crossref PubMed Scopus (155) Google Scholar). There is no evidence for neurodegeneration in DYT1 dystonia, implying that abnormal movements are caused by a functional neuronal defect (4Rostasy K. Augood S.J. Hewett J.W. Leung J.C. Sasaki H. Ozelius L.J. Ramesh V. Standaert D.G. Breakefield X.O. Hedreen J.C. Neurobiol. Dis. 2003; 12: 11-24Crossref PubMed Scopus (138) Google Scholar). All cases of typical DYT1 dystonia are caused by an in-frame GAG deletion (ΔGAG302/303; ΔE) in DYT1 gene, resulting in the loss of a glutamic acid in the C-terminal region of the encoded protein, torsinA (1Ozelius L.J. Hewett J.W. Page C.E. Bressman S.B. Kramer P.L. Shalish C. de Leon D. Brin M.F. Raymond D. Corey D.P. Fahn S. Risch N.J. Buckler A.J. Gusella J.F. Breakefield X.O. Nat. Genet. 1997; 17: 40-48Crossref PubMed Scopus (900) Google Scholar). TorsinA is a member of the AAA ATPase superfamily of chaperone-like proteins (5Neuwald A.F. Aravind L. Spouge J.L. Koonin E.V. Genome Res. 1999; 9: 27-43Crossref PubMed Google Scholar). In mammalian neuronal cells, torsinA is found throughout the cytoplasm, neurite processes, and growth cones (6Kamm C. Boston H. Hewett J. Wilbur J. Corey D.P. Hanson P.I. Ramesh V. Breakefield X.O. J. Biol. Chem. 2004; 279: 19882-19892Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 7Hewett J. Gonzalez-Agosti C. Slater D. Ziefer P. Li S. Bergeron D. Jacoby D.J. Ozelius L.J. Ramesh V. Breakefield X.O. Hum. Mol. Genet. 2000; 9: 1403-1413Crossref PubMed Scopus (176) Google Scholar). TorsinA has also been found in the lumen of the endoplasmic reticulum (ER) 3The abbreviations used are: ERendoplasmic reticulumSNAREsoluble N-ethylmaleimide-sensitive factor attachment protein receptorwtwild typeNEnuclear envelopeSVsynaptic vesicleHAhemagglutininGFPgreen fluorescent proteinPDIprotein-disulfide isomeraseGSTglutathione S-transferasePBSphosphate-buffered salineBSAbovine serum albuminCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidPFAparaformaldehydesiRNAsmall interfering RNASytIsynaptotagmin ISGIsecretogranin I. and in the space between the inner and the outer membrane of the nuclear envelope (NE) (8Hewett J. Ziefer P. Bergeron D. Naismith T. Boston H. Slater D. Wilbur J. Schuback D. Kamm C. Smith N. Camp S. Ozelius L.J. Ramesh V. Hanson P.I. Breakefield X.O. J. Neurosci. Res. 2003; 72: 158-168Crossref PubMed Scopus (99) Google Scholar, 9Liu Z. Zolkiewska A. Zolkiewski M. Biochem. J. 2003; 374: 117-122Crossref PubMed Scopus (60) Google Scholar, 10Callan A.C. Bunning S. Jones O.T. High S. Swanton E. Biochem. J. 2006; 401: 607-612Crossref Scopus (44) Google Scholar, 11Kustedjo K. Bracey M.H. Cravatt B.F. J. Biol. Chem. 2000; 275: 27933-27939Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). In contrast, in cells overexpressing the mutant (ΔE-torsinA), the protein is redistributed from ER to NE and accumulates in large perinuclear membranous inclusions, which appeared to arise from the nuclear envelope (7Hewett J. Gonzalez-Agosti C. Slater D. Ziefer P. Li S. Bergeron D. Jacoby D.J. Ozelius L.J. Ramesh V. Breakefield X.O. Hum. Mol. Genet. 2000; 9: 1403-1413Crossref PubMed Scopus (176) Google Scholar, 12Goodchild R.E. Dauer W.T. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 847-852Crossref PubMed Scopus (225) Google Scholar, 13Naismith T.V. Heuser J.E. Breakefield X.O. Hanson P.I. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7612-7617Crossref PubMed Scopus (191) Google Scholar, 14Misbahuddin A. Placzek M.R. Taanman J.W. Gschmeissner S. Schiavo G. Cooper J.M. Warner T.T. Mov. Disord. 2005; 20: 432-440Crossref PubMed Scopus (44) Google Scholar). TorsinA-positive inclusions have been found in the midbrain of DYT1 patients, suggesting that they are relevant to the pathogenesis of DYT1 dystonia (15McNaught K.S. Kapustin A. Jackson T. Jengelley T.A. Jnobaptiste R. Shashidharan P. Perl D.P. Pasik P. Ann. Neurol. 2004; PubMed Scopus Google Scholar). In SH-SY5Y neuroblastoma cells, inclusions the a protein in A. Placzek M.R. Taanman J.W. Gschmeissner S. Schiavo G. Cooper J.M. Warner T.T. Mov. Disord. 2005; 20: 432-440Crossref PubMed Scopus (44) Google Scholar). evidence for abnormal function in DYT1 dystonia from that torsinA affects the membrane of the and the of in a J.M. Shashidharan P. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google Scholar, A. G. A. P. N. G. Standaert D.G. Neurobiol. Dis. 2006; PubMed Scopus Google Scholar). with these observations, torsinA is in of the S.J. Ozelius L.J. Breakefield X.O. Standaert D.G. Ann. Neurol. 1999; PubMed Scopus Google Scholar, P. Kramer Brin M.F. Res. 2000; PubMed Scopus Google Scholar). in a DYT1 has that mutant torsinA A. N. Breakefield X.O. Standaert D.G. J. PubMed Scopus Google Scholar). endoplasmic reticulum N-ethylmaleimide-sensitive factor attachment protein wild type nuclear envelope synaptic vesicle fluorescent protein serum acid small interfering synaptotagmin I I. the role of torsinA we a using and ΔE-torsinA as a associated protein of protein J.M. S. Nat. Neurosci. 1999; PubMed Scopus Google was and its with both wild type and mutant torsinA by in and in Snapin is to the of synaptic by interacting with of the SNARE complex J.M. S. Nat. Neurosci. 1999; PubMed Scopus Google Scholar, U. P. J. Nat. Biol. PubMed Scopus Google Scholar). In view of this we overexpression of wild type mutant torsinA affects recycling in SH-SY5Y cells. to the functional between torsinA and snapin, we the effects of of both findings suggest that overexpression of as as of the endogenous torsinA negatively affects ΔE-torsinA to as a loss of function mutant by synaptic membrane and from The antibody is from the antibody was against a to the of synaptotagmin I and fluorescent protein from R. M. C. R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google and T. The and by T. H. of and by H. of The torsinA antibody is from the antibody is from the is from and the torsinA is from and and from from and was from with containing wild type DYT1 no A. Placzek M.R. Taanman J.W. Gschmeissner S. Schiavo G. Cooper J.M. Warner T.T. Mov. Disord. 2005; 20: 432-440Crossref PubMed Scopus (44) Google in of and serum and was used to the the DYT1 and in-frame the and of the The was which was with with an for growth on was and in using and was using the of the from was in cells, and for using the to the and of DYT1 and and deletion by from and the C-terminal deletion mutant of snapin from from J. U. P. J. Nat. Biol. PubMed Scopus Google and and of as snapin to was by R. M. C. R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). was in E. by the of for G. J. C. G. J. Sci. 1999; PubMed Google Scholar). of the in and protein proteins on for with containing and in torsinA and its mutant against and snapin and its against In and proteins containing snapin, and its deletion to in containing for The with in for and with proteins using on for and with proteins for in with containing and in proteins analyzed by The was with to the SH-SY5Y wild type torsinA and ΔE-torsinA in and in and containing for with with the proteins in and analyzed by and from SH-SY5Y wild type as with of of antibody for of a the with an antibody to and for with containing the in and analyzed in by with and of SH-SY5Y cells wild type the in and analyzed by with I by by and using of in containing on in of was to and the for with The cells for and in growth and to on with for The the growth was with and The cells analyzed for and to PC12 cells on and with factor in for J. T. Schiavo G. Mol. Biol. 12: PubMed Scopus Google Scholar). The cells with in for SH-SY5Y with and with for The cells and containing serum was for PC12 cells in and for and in containing and serum and for with for and in for The and with with on cells and cells was for with and as The by with a cells ΔE-torsinA with by to the for by in for The cells in in and in and using an G. G. J.W. of in Scholar). with and protein The PC12 cells in and as The for and V. de H. J. J. PubMed Scopus Google Scholar). snapin was using and protein The in a and the with an and exo-endocytic The M. K. P. J. Biol. PubMed Scopus Google is on a antibody against the of The antibody was in containing with and to the cells. the cells with in and with containing The cells with and The by using a with the The was and for for of the cells was using The is on the uptake and of the dye FM1-43 in SH-SY5Y cells wild type SH-SY5Y on with FM1-43 dye in for by of with and by with to the FM1-43 was to the cells in of and in the of acid with a with a The was by a and was using The of cells for in was using of for torsinA and snapin used to gene cells using of in the was with and the cells used The cells with used as of torsinA and/or snapin was by and using and as was using of type and a to proteins that with both wild type torsinA and mutant torsinA DYT1 and its mutant used as to an a using and using using ΔE-torsinA as a encoded for the C-terminal region of snapin, a synaptic protein in the of J.M. S. Nat. Neurosci. 1999; PubMed Scopus Google Scholar). The of and ΔE-torsinA with snapin was by an The of was and with that of a with and its partner (6Kamm C. Boston H. Hewett J. Wilbur J. Corey D.P. Hanson P.I. Ramesh V. Breakefield X.O. J. Biol. Chem. 2004; 279: 19882-19892Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). in the of the of with snapin and was was found between the of snapin with and in and ΔE-torsinA as proteins to in snapin the of the no of snapin with was the in this a of of and snapin and in for and to its and the the C-terminal region to In contrast, a containing both and the of of the proteins This that the is in this and the is for the with In with the in no was observed in snapin between and its mutant In a snapin and its C-terminal as to both and ΔE-torsinA In contrast, no to was This that the region of snapin is to the with both wild type and mutant torsinA. was also using from SH-SY5Y cells and ΔE-torsinA with an of with both wild type and mutant torsinA was using an antibody Snapin appeared to ΔE-torsinA and no was with The of the endogenous snapin to with and was also analyzed by from from SH-SY5Y cells and with the in snapin was to both and mutant torsinA. In contrast, no was using a antibody Snapin with TorsinA in SH-SY5Y the between torsinA and snapin in cells, we an in SH-SY5Y cells overexpressing torsinA using against endogenous snapin and the of torsinA. the snapin with synaptotagmin I a of and and this is by the overexpression of ΔE-torsinA in these cells, endogenous snapin also accumulates in the typical inclusions a by Snapin with torsinA on the NE a of of ΔE-torsinA M.R. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, R.E. C.E. Dauer W.T. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). We also analyzed the of snapin in SH-SY5Y overexpressing The cellular of both snapin and the of of to the between these proteins in the ER a torsinA (8Hewett J. Ziefer P. Bergeron D. Naismith T. Boston H. Slater D. Wilbur J. Schuback D. Kamm C. Smith N. Camp S. Ozelius L.J. Ramesh V. Hanson P.I. Breakefield X.O. J. Neurosci. Res. 2003; 72: 158-168Crossref PubMed Scopus (99) Google Scholar, 9Liu Z. Zolkiewska A. Zolkiewski M. Biochem. J. 2003; 374: 117-122Crossref PubMed Scopus (60) Google Scholar, 10Callan A.C. Bunning S. Jones O.T. High S. Swanton E. Biochem. J. 2006; 401: 607-612Crossref Scopus (44) Google we with the ER and This a of of torsinA and snapin in this and in the of protein by caused the loss of between snapin and the between snapin and and in the of and in suggest that in SH-SY5Y cells, and snapin are co-localized both in the and in a of ER proteins and containing such as Snapin and TorsinA on in this we analyzed the of endogenous torsinA and snapin using in PC12 cells for with factor torsinA and snapin a in the and with the neurite and was the endogenous proteins similar in primary with in both the and the of PC12 cells using a to the in of the V. de H. J. J. PubMed Scopus Google and endogenous snapin by with antibody with protein associated to a of dense core granules the neurite and was on dense core granules with protein on the the antibody was to endogenous torsinA by and the antibody was with the for that the of torsinA and snapin was to these PC12 cells for a in torsinA and snapin and in other for snapin suggesting that neurite a of which may both TorsinA the view of suggesting the of torsinA in J.M. Shashidharan P. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google and the role of snapin in J.M. S. Nat. Neurosci. 1999; PubMed Scopus Google Scholar, M. L. Li C. C. U. D. C. J. J. Neurosci. 2005; PubMed Scopus Google we torsinA a role in this we an in SH-SY5Y cells, using an antibody against the intravesicular of This antibody is of the with the membrane, which the of the of on the M. K. P. J. Biol. PubMed Scopus Google Scholar, M. S. U. C. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the with this antibody in and the of on the plasma membrane exocytosis and SH-SY5Y cells with and ΔE-torsinA with the antibody in and and The cells and with a to of was the of on the of cells was in cells In SH-SY5Y cells overexpressing on the plasma membrane on was with the cells suggesting that overexpression of torsinA In contrast, cells overexpressing ΔE-torsinA a of on the plasma membrane in which overexpression of ΔE-torsinA to affect the of vesicle in SH-SY5Y cells, resulting in an of on the plasma membrane and of membrane The of membrane recycling in and cells may on an of which by overexpression of and by We the of and of and in SH-SY5Y cells and in cells and ΔE-torsinA the of in the both in and and was in cells cells and was in cells findings suggest that torsinA is to the of the to the of vesicle such as a of In the of these we to using FM1-43 uptake A.J. Neurosci. 1999; 1-10Crossref PubMed Scopus Google Scholar, A.C. J.L. 2004; PubMed Scopus Google Scholar). This dye exocytosis and in cells, a of these in In SH-SY5Y cells a ΔE-torsinA for to the dye in to in and and The was and the of the uptake is in We found that FM1-43 uptake is in cells and in cells with SH-SY5Y cells the of cells with resulting in a and loss and cells used as the was in the mutant and in the SH-SY5Y cells the the was for the the and of FM1-43 was in and mutant cells suggesting that exocytosis is by and ΔE-torsinA that FM1-43 was to we the in the of and This FM1-43 that in SH-SY5Y cells is of the Knockdown of TorsinA and Snapin on and the role of torsinA and snapin in the of an was SH-SY5Y cells with a of for torsinA snapin a of and the of the was by and torsinA and snapin was by of the and In the the of both snapin and torsinA was by and a cells with and no effect on torsinA snapin was observed and in cells with was analyzed to the in of cells with snapin a in to with the to and In contrast, cells with torsinA a for on the to which on and this cells overexpressing mutant torsinA and suggesting that ΔE-torsinA is a loss of function mutant. with both had an inhibitory resulting in a of on the membrane similar to the snapin and This that snapin is to from torsinA in the of of the with both for torsinA and snapin also analyzed for FM1-43 uptake in and and and The in that with both torsinA snapin and snapin negatively the uptake of FM1-43 with similar This that torsinA and snapin on the and is to a of endocytosis. snapin, both proteins in a of FM1-43 with cells, the was for the that endogenous of torsinA and snapin are also for regulated In the study, we used to a partner of the protein We have that snapin a with wild type and mutant torsinA. has been that the is for torsinA function and cellular (6Kamm C. Boston H. Hewett J. Wilbur J. Corey D.P. Hanson P.I. Ramesh V. Breakefield X.O. J. Biol. Chem. 2004; 279: 19882-19892Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 13Naismith T.V. Heuser J.E. Breakefield X.O. Hanson P.I. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 7612-7617Crossref PubMed Scopus (191) Google Scholar). we have that this of torsinA and/or the region has the role of This of is from that for which the region of torsinA for (6Kamm C. Boston H. Hewett J. Wilbur J. Corey D.P. Hanson P.I. Ramesh V. Breakefield X.O. J. Biol. Chem. 2004; 279: 19882-19892Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). have been for in the NE and a protein in the ER R.E. Dauer W.T. J. Biol. 2005; PubMed Scopus Google Scholar). suggest that torsinA may have in cellular that endogenous torsinA with snapin on granules In cells overexpressing of snapin was also in perinuclear membrane Snapin is a protein, which was found to associated with binds the SNARE complex by a with The of snapin to the SNARE complex is to to the between the and J.M. S. Nat. Neurosci. 1999; PubMed Scopus Google Scholar). This association is a in the of which to the of with the plasma membrane by J. D. Biol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). by snapin for in U. P. J. Nat. Biol. PubMed Scopus Google Scholar, P. J. J. Neurosci. 2004; PubMed Scopus Google Scholar). evidence the role of snapin in M. C. R. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google of a snapin a role for this protein in M. L. Li C. C. U. D. C. J. J. Neurosci. 2005; PubMed Scopus Google Scholar). In the study, snapin was also to associated with with other such as and other proteins have been as interacting of snapin in both neuronal and cells P. A. I. E. T. Biochem. J. 2003; PubMed Scopus Google Scholar). are in membrane is in the of as of large dense core exocytosis in PC12 and the with snapin its from to the plasma membrane C. T. I. R. A. R. A. Mol. Biol. 2005; PubMed Google Scholar, M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, C. R. N. A. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). with these that snapin has a effect on the exo-endocytic with a in vesicle and a in the uptake and of The of torsinA with snapin the that torsinA may in in of the effects of torsinA on in SH-SY5Y with wild type DYT1 and that overexpressing negatively affects as by the of FM1-43 uptake In contrast, ΔE-torsinA appeared to membrane recycling the of the of the of vesicle such as from the plasma Knockdown of torsinA a similar to snapin, resulting in a inhibitory effect on the exo-endocytic the of both proteins the effect of with the that torsinA and snapin a role in the the effect of torsinA resembles the caused by ΔE-torsinA this is the that ΔE-torsinA is a loss of function evidence of the mutation may affect torsinA function and its pathological findings that torsinA plays a role in the recycling of membrane, which of This the between torsinA and abnormal which may affect the J.M. Shashidharan P. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: PubMed Scopus Google that is to the of such as the the of A. Placzek M.R. Taanman J.W. Gschmeissner S. Schiavo G. Cooper J.M. Warner T.T. Mov. Disord. 2005; 20: 432-440Crossref PubMed Scopus (44) Google that ΔE-torsinA inclusions which is for of have been in the pathogenesis of dystonic movements from of other of dystonia with P. Marsden C.D. Ann. Neurol. 1998; PubMed Scopus Google and A. T. Mov. Disord. PubMed Scopus Google Scholar). In addition, in a of DYT1 dystonia found an abnormal between the and the A. G. A. P. N. G. Standaert D.G. Neurobiol. Dis. 2006; PubMed Scopus Google and abnormal has been in DYT1 A. N. Breakefield X.O. Standaert D.G. J. PubMed Scopus Google Scholar). is in torsinA is in of the S.J. Ozelius L.J. Breakefield X.O. Standaert D.G. Ann. Neurol. 1999; PubMed Scopus Google Scholar). suggest that torsinA and snapin a role in the responsible for of is is that torsinA may have a chaperone-like function S. Hum. Mol. Genet. 2003; 12: PubMed Scopus Google Scholar, J. Neurobiol. 2006; PubMed Scopus Google the of proteins in such torsinA with N-ethylmaleimide-sensitive protein (5Neuwald A.F. Aravind L. Spouge J.L. Koonin E.V. Genome Res. 1999; 9: 27-43Crossref PubMed Google an AAA-ATPase for that is responsible for SNARE recycling P.I. Heuser J.E. R. Neurobiol. 1997; PubMed Scopus Google Scholar). torsinA may to snapin which is for its function U. P. J. Nat. Biol. PubMed Scopus Google Scholar). snapin may the association of torsinA with and This is with in association of torsinA with in the S.J. Ozelius L.J. Breakefield X.O. Standaert D.G. Ann. Neurol. 1999; PubMed Scopus Google and with findings that torsinA and snapin with the granules in PC12 cells. In to these which are the effects of torsinA on suggest that may also of membrane on snapin The pathogenesis of ΔE-torsinA The of membranous caused by of ΔE-torsinA is in and SH-SY5Y cells (7Hewett J. Gonzalez-Agosti C. Slater D. Ziefer P. Li S. Bergeron D. Jacoby D.J. Ozelius L.J. Ramesh V. Breakefield X.O. Hum. Mol. Genet. 2000; 9: 1403-1413Crossref PubMed Scopus (176) Google Scholar, 14Misbahuddin A. Placzek M.R. Taanman J.W. Gschmeissner S. Schiavo G. Cooper J.M. Warner T.T. Mov. Disord. 2005; 20: 432-440Crossref PubMed Scopus (44) Google has been also observed in other overexpressing ΔE-torsinA inclusions to from the NE P. J. Neurosci. 2004; PubMed Scopus Google and have been in DYT1 a role in the pathogenesis of dystonia (15McNaught K.S. Kapustin A. Jackson T. Jengelley T.A. Jnobaptiste R. Shashidharan P. Perl D.P. Pasik P. Ann. Neurol. 2004; PubMed Scopus Google Scholar). inclusions have also been in ΔE-torsinA N. J. A. Standaert D.G. Breakefield X.O. J. Neurosci. 2005; PubMed Scopus Google Scholar, P. D. U. K.S. D. T. Brin M.F. Hum. Mol. Genet. 2005; PubMed Scopus Google Scholar). In addition, the that the of torsinA is similar to the that the loss of torsinA function plays an in the K.S. Jengelley T.A. Jackson T. Li J. Li Neurol. 2005; PubMed Scopus Google Scholar). This is by that overexpression of ΔE-torsinA and of endogenous torsinA to the of on the plasma In suggest that torsinA has a role in vesicle The mutation torsinA from membrane and the of proteins on the This in may the neuronal in the of The by which ΔE-torsinA exerts its effect of proteins in such snapin and the membranous ΔE-torsinA to the of torsinA from other cellular interfering with its of these in this may the of a functional in We A. for and S. and S. for of the with