NAF Ataxia Research Studies Currently Underway

Chih-Cheng Tsai, PhD

UMDNJ-Robert Wood Johnson Medical School
Mechanisms of ataxin-1 mediated cytotoxicity

Summary: My research focuses on ataxin-1, whose glutamine-repeat expanded form causes SCA 1. Although researchers have long thought that insoluble ataxin-1 aggregates are the main culprits for bringing about SCA 1 symptoms, this view has recently been challenged by findings that the detrimental effects of ataxin-1 begin appearing before protein aggregates form, or even when aggregates do not form at all. These observations were made in mice or in fruit flies (Drosophila) that were genetically engineered to express mutant ataxin-1. Such evidence has led many researchers to look once again for what makes mutant ataxin-1 so toxic to certain cells. We recently found that ataxin-1 binds an important nuclear protein called SMRT (Silencing Mediator or Retinoid and Thyroid hormone receptors) in vertebrate cells; it also binds to a SMRT -related factor, called SMRTER, in flies. Because the main property of SMRT and SMRTER is to help other proteins, such as thyroid hormone receptor in vertebrates or ecdysone receptor in flies, to shut down the transcription of their target genes, the physical interaction we observed between ataxin-1 and SMRT/SMRTER leads us to hypothesize that mutant ataxin-1 may damage cells because of its ability to perturb nuclear receptor signaling pathways. Because ataxin-1 can interact with SMRTER, and because Drosophila nuclear receptors, like their vertebrate counterparts, use similar methods to regulate gene expression, we propose to use fly as a model system for investigating the relationships among ataxin-1, SMRTER, and nuclear horm9ne receptors in living organisms. If our studies in flies show promising results, it would help us to design better parallel experiments in vertebrate cells and in live vertebrate animals (where research is much more time-consuming) to see whether the cytotoxicity caused by mutant ataxin-1 is indeed due to disrupted nuclear receptor signaling. Many of these nuclear receptors bind steroid, thyroid, or retinoid hormones; if their properties are indeed affected by mutant ataxin-1, it is possible that drugs that affect the operation of these nuclear receptors could be used to counteract the damaging effects brought about by SCA 1.