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     The first goal of my laboratory is to understand the biological basis of disorders caused by dysfunction of the basal ganglia and use that knowledge to develop novel therapies for this group of neurological diseases. Currently, studies in my lab focus on a disease known as DYT1 dystonia, the most common form of inherited dystonia. DYT1 dystonia, a dominantly inherited, incurable disease, is caused by a three-nucleotide deletion in the gene TOR1A that causes the loss of a glutamic acid in the protein torsinA. TorsinA is a AAA protein (ATPases Associated with diverse cellular Activities) that resides primarily in the endoplasmic reticulum. However, our lab and others demonstrated that torsinA carrying the disease-causing mutation accumulates abnormally in the nuclear envelope.

Over the next few years, my laboratory will focus on DYT1 dystonia research through the following major projects:    

   1) Define the biological role of torsinA and its role in DYT1pathogenesis

    2) Understand how the neuronal protein quality control machinery “handles” torsinA and the

        significance of this process in disease pathogenesis

    3) Development of therapeutic RNAi interference for DYT1 dystonia. In addition to enhancing our

       knowledge on the pathogenesis of dystonia and related disorders, these studies will contribute to

       exploit RNA interference as a therapy for DYT1 and other incurable neurological diseases.

     A second objective of our research is to understand the role of neuronal protein quality control in aging. We have very recently started experiments aimed to determine the causes and consequences of cellular aging or senescence. There is experimental evidence indirectly implicating dysfunction of protein homeostasis in aging. It has also been proposed that the nervous system plays an important role in the regulation of this phenomenon. We hypothesize that progressive age-related defects in neuronal protein homeostasis play an important role in mammalian aging, both in a cell-autonomous and non-cell-autonomous manner. To test this hypothesis, we are currently generating transgenic mice in which we aim to accelerate neuronal aging through the manipulation of protein homeostasis.