The first two authors contributed equally to this work.
TorsinA in PC12 cells: Localization in the endoplasmic reticulum and response to stress
Article first published online: 19 FEB 2003
Copyright © 2003 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 72, Issue 2, pages 158–168, 15 April 2003
How to Cite
Hewett, 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. and Breakefield, X. O. (2003), TorsinA in PC12 cells: Localization in the endoplasmic reticulum and response to stress. J. Neurosci. Res., 72: 158–168. doi: 10.1002/jnr.10567
- Issue published online: 27 MAR 2003
- Article first published online: 19 FEB 2003
- Manuscript Accepted: 26 NOV 2002
- Manuscript Revised: 22 NOV 2002
- Manuscript Received: 19 AUG 2002
- NINDS. Grant Numbers: NS28384, NS38142, NS37409
- oxidative stress;
- endoplasmic reticulum;
- movement disorders;
- cell morphology
Most cases of early-onset torsion dystonia are caused by deletion of GAG in the coding region of the DYT1 gene encoding torsinA. This autosomal dominant neurologic disorder is characterized by abnormal movements, believed to originate from neuronal dysfunction in the basal ganglia of the human brain. The torsins (torsinA and torsinB) are members of the “ATPases associated with a variety of cellular activities” (AAA+) superfamily of proteins that mediate chaperone and other functions involved in conformational modeling of proteins, protection from stress, and targeting of proteins to cellular organelles. In this study, the intracellular localization and levels of endogenous torsin were evaluated in rat pheochromocytoma PC12 cells following differentiation and stress. TorsinA, apparent MW 37 kDa, cofractionates with markers for the microsomal/endoplasmic reticulum (ER) compartment and appears to reside primarily within the ER lumen based on protease resistance. TorsinA immunoreactivity colocalizes with the lumenal ER protein protein disulfide isomerase (PDI) and extends throughout neurites. Levels of torsinA did not increase notably in response to nerve growth factor-induced differentiation. None of the stress conditions tested, including heat shock and the unfolded protein response, affected torsinA, except for oxidative stress, which resulted in an increase in the apparent MW of torsinA and redistribution to protrusions from the cell surface. These findings are consistent with a relatively rapid covalent modification of torsinA in response to oxidative stress causing a change in state. Mutant torsinA may interfere with and/or compromise ER functions, especially in dopaminergic neurons, which have high levels of torsinA and are intrinsically vulnerable to oxidative stress. © 2003 Wiley-Liss, Inc.