The AAA+ ATPase enzyme TorsinA (TorA) is mutated in the hereditary neurological disorder, early onset torsion dystonia. TorA is expressed in all tissues of the body, yet neurons exhibit a particular sensitivity to mutation of the enzyme. It has been demonstrated that mutant forms of TorA enrich in the nuclear envelope (NE), and knockout/disease knockin mice have deformed NEs, suggesting that TorA's disease-relevant function is in the NE. We have uncovered a cofactor-driven mechanism by which wild type TorA is induced to enrich in this compartment. At the NE, TorA displaces specific NE resident proteins and deforms NE membranes. The disease-mutant form of TorA is very inefficient at enacting these changes at the NE, suggesting possible functional deficiencies in dystonia. This proposal aims to characterize the interaction between TorA and this cofactor, LULL1, in order to understand how TorA is induced to redistribute to the NE by LULL1. Understanding the molecular control and cellular regulation of TorA's redistribution to the NE will shed light on the possible mechanism of early-onset torsion dystonia. This work may also provide a paradigm for understanding the etiology of other nuclear envelope-associated hereditary diseases. In accordance with the mission of the NIH, the main goal of these Aims is to understand the cellular function of a disease-associated protein in order to gain an understanding of the molecular mechanism of a disease.
| Goodchild, Rose E; Buchwalter, Abigail L; Naismith, Teresa V et al. (2015) Access of torsinA to the inner nuclear membrane is activity dependent and regulated in the endoplasmic reticulum. J Cell Sci 128:2854-65 |
| Vander Heyden, Abigail B; Naismith, Teresa V; Snapp, Erik L et al. (2011) Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum. EMBO J 30:3217-31 |
| Vander Heyden, Abigail B; Naismith, Teresa V; Snapp, Erik L et al. (2009) LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol Biol Cell 20:2661-72 |
