 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, March 17, 2004, 24(11):2593-2601; doi:10.1523/JNEUROSCI.4461-03.2004
Previous Article | Next Article
Neurobiology of Disease
Aberrant Cellular Behavior of Mutant TorsinA Implicates Nuclear Envelope Dysfunction in DYT1 Dystonia
Pedro Gonzalez-Alegre andHenry L. Paulson Department of Neurology, Carver College of Medicine at the University of Iowa, Iowa City, Iowa 52242
Torsion dystonia-1 (DYT1) dystonia, the most common inherited form of dystonia, is caused by a three base pair deletion that eliminates a single amino acid from the disease protein, torsinA. TorsinA is an "AAA" protein thought to reside in the endoplasmic reticulum (ER), yet both its cellular function and the basis for neuronal dysfunction in DYT1 remain unknown. A clue to disease pathogenesis is the fact that mutant, but not wild-type, torsinA forms membranous inclusions in cell culture. To explore the pathobiology of DYT1 dystonia, we generated PC12 neural cell lines that inducibly express wild-type or mutant torsinA. Although in this model torsinA displays some properties consistent with ER localization, mutant torsinA also accumulates in the nuclear envelope (NE), a structure contiguous with cytoplasmic ER. Consistent with this, membranous inclusions formed by mutant torsinA are shown to derive not from the ER, as thought previously, but from the NE. We demonstrate further that torsinA forms different disulfide-linked complexes that may be linked functionally to subcellular localization in the NE versus cytoplasmic ER. Despite mutant TA accumulation in NE structures, nucleocytoplasmic transport of a reporter protein was unaffected. These findings, together with parallel studies failing to demonstrate perturbation of ER function, implicate the NE as a primary site of dysfunction in DYT1. DYT1 dystonia can be added to the growing list of inherited neurological disorders involving the NE.
Key words: dystonia; torsinA; DYT1; nuclear envelope; karmellas; endoplasmic reticulum
Received Oct 1, 2003; revised January 14, 2004; accepted January 23, 2004.
This article has been cited by other articles:
T. V. Naismith, S. Dalal, and P. I. Hanson
Interaction of TorsinA with Its Major Binding Partners Is Impaired by the Dystonia-associated {Delta}GAG Deletion
J. Biol. Chem., October 9, 2009; 284(41): 27866 - 27874.
[Abstract] [Full Text] [PDF]
L. M. Giles, L. Li, and L.-S. Chin
Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis
J. Biol. Chem., August 7, 2009; 284(32): 21765 - 21775.
[Abstract] [Full Text] [PDF]
A. B. Vander Heyden, T. V. Naismith, E. L. Snapp, D. Hodzic, and P. I. Hanson
LULL1 Retargets TorsinA to the Nuclear Envelope Revealing an Activity That Is Impaired by the DYT1 Dystonia Mutation
Mol. Biol. Cell, June 1, 2009; 20(11): 2661 - 2672.
[Abstract] [Full Text] [PDF]
B Zirn, K Grundmann, P Huppke, J Puthenparampil, H Wolburg, O Riess, and U Muller
Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1)
J. Neurol. Neurosurg. Psychiatry, December 1, 2008; 79(12): 1327 - 1330.
[Abstract] [Full Text] [PDF]
F. C. Nery, J. Zeng, B. P. Niland, J. Hewett, J. Farley, D. Irimia, Y. Li, G. Wiche, A. Sonnenberg, and X. O. Breakefield
TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton
J. Cell Sci., October 15, 2008; 121(20): 3476 - 3486.
[Abstract] [Full Text] [PDF]
L. M. Giles, J. Chen, L. Li, and L.-S. Chin
Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope
Hum. Mol. Genet., September 1, 2008; 17(17): 2712 - 2722.
[Abstract] [Full Text] [PDF]
A. Granata, R. Watson, L. M. Collinson, G. Schiavo, and T. T. Warner
The Dystonia-associated Protein TorsinA Modulates Synaptic Vesicle Recycling
J. Biol. Chem., March 21, 2008; 283(12): 7568 - 7579.
[Abstract] [Full Text] [PDF]
C. T. Esapa, A. Waite, M. Locke, M. A. Benson, M. Kraus, R.A. J. McIlhinney, R. V. Sillitoe, P. W. Beesley, and D. J. Blake
SGCE missense mutations that cause myoclonus-dystonia syndrome impair {varepsilon}-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA
Hum. Mol. Genet., February 1, 2007; 16(3): 327 - 342.
[Abstract] [Full Text] [PDF]
N. Kock, T. V. Naismith, H. E. Boston, L. J. Ozelius, D. P. Corey, X. O. Breakefield, and P. I. Hanson
Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier
Hum. Mol. Genet., April 15, 2006; 15(8): 1355 - 1364.
[Abstract] [Full Text] [PDF]
P. Gonzalez-Alegre, N. Bode, B. L. Davidson, and H. L. Paulson
Silencing Primary Dystonia: Lentiviral-Mediated RNA Interference Therapy for DYT1 Dystonia
J. Neurosci., November 9, 2005; 25(45): 10502 - 10509.
[Abstract] [Full Text] [PDF]
N. Sharma, M. G. Baxter, J. Petravicz, D. C. Bragg, A. Schienda, D. G. Standaert, and X. O. Breakefield
Impaired Motor Learning in Mice Expressing TorsinA with the DYT1 Dystonia Mutation
J. Neurosci., June 1, 2005; 25(22): 5351 - 5355.
[Abstract] [Full Text] [PDF]
S. Cao, C. C. Gelwix, K. A. Caldwell, and G. A. Caldwell
Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons of Caenorhabditis elegans
J. Neurosci., April 13, 2005; 25(15): 3801 - 3812.
[Abstract] [Full Text] [PDF]
P. Shashidharan, D. Sandu, U. Potla, I.A. Armata, R.H. Walker, K.S. McNaught, D. Weisz, T. Sreenath, M.F. Brin, and C.W. Olanow
Transgenic mouse model of early-onset DYT1 dystonia
Hum. Mol. Genet., January 1, 2005; 14(1): 125 - 133.
[Abstract] [Full Text] [PDF]
L. Gerace
TorsinA and torsion dystonia: Unraveling the architecture of the nuclear envelope
PNAS, June 15, 2004; 101(24): 8839 - 8840.
[Full Text] [PDF]
|
|
|
|
 |
|