My long-term career goal is to understand the biological abnormalities underlying neurological disorders and apply that knowledge to improve the quality of life of patients suffering from them. During my training period, I developed a strong interest on the inherited dystonias. Dystonia is a neurological syndrome characterized by prolonged twisting involuntary movements that are frequently stereotyped. Several genetic forms of dystonia have been described, being DYT1 the most common. I initially became specially interested and studied DYT1 dystonia during my postdoctoral training. I now need to acquire skills necessary to assess the normal function of torsinA, the protein mutated in DYT1, and its dysfunction in the disease state in cultured cells and animal models. To accomplish this goal, I have developed collaborations with several scientists and will pursue the proposed work within the Department of Neurology at The University of Iowa. TorsinA is one of four closely related mammalian torsin proteins. A recent breakthrough in DYT1 research demonstrated that, while normally residing in the endoplasmic reticulum (ER), mutant torsinA accumulates in the nuclear envelope (NE). From this location, torsinA has been found to modulate aggregation of cytoplasmic proteins into aggresomes. What is the role of torsinA in the nuclear envelope, how leads to neuronal dysfunction when mutated, how modulates aggresome and what factors condition the reduced penetrance of the disease remain unanswered questions. Building on recent reports and my own preliminary results, I will directly address those questions.
In Aim 1, I will determine how torsinA modulates the dynamic behavior of NE proteins and influences the protein composition of this subcellular structure.
In Aim 2, I will use a novel dynamic microscopy system and basic biological techniques to define how torsinA influences aggresome formation.
In Aim 3, I will use RNA interference to simultaneously silence the different torsin gene family members in cultured cells and in vivo to determine their potential role as modulators of torsinA-induced dysfunction. This project will yield important information concerning the function of torsinA, and may uncover the factors that modify the reduced penetrance of DYT1 dystonia, providing therapeutic strategies to prevent the development of the disease in all mutation carriers. This proposal exemplifies the type of clinically related fundamental neurobiological research I plan to pursue during my career. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Scientist Development Award - Research (K02)
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NST-2 Subcommittee (NST)
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Tagle, Danilo A
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University of Iowa
Schools of Medicine
Iowa City
United States
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Gordon, K L; Glenn, K A; Bode, N et al. (2012) The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy. Neuroscience 224:160-71
Maric, Martina; Shao, Jianqiang; Ryan, Randi J et al. (2011) A functional role for TorsinA in herpes simplex virus 1 nuclear egress. J Virol 85:9667-79
Gordon, Kara L; Glenn, Kevin A; Gonzalez-Alegre, Pedro (2011) Exploring the influence of torsinA expression on protein quality control. Neurochem Res 36:452-9
Page, Michelle E; Bao, Li; Andre, Pierrette et al. (2010) Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (DeltaE) TorsinA in transgenic mice. Neurobiol Dis 39:318-26
Martin, J N; Bair, T B; Bode, N et al. (2009) Transcriptional and proteomic profiling in a cellular model of DYT1 dystonia. Neuroscience 164:563-72
Gordon, K L; Gonzalez-Alegre, P (2008) Consequences of the DYT1 mutation on torsinA oligomerization and degradation. Neuroscience 157:588-95