Research Grant Award

Michael D. Hebert, PhD

The University of Mississippi Medical Center, Jackson, MS
Disrupted pre-mRNA splicing in Machado-Joseph disease

The cell nucleus is highly organized and contains distinct domains, territories and bodies. Many of these structures participate in the efficient production and processing of RNA. Disruptions in this process will impede the flow of information from DNA to RNA to protein and lead to cell death. Several neurodegenerative disorders, such as Huntington's disease, spinocerebellar ataxia-type 1 and Machado-Joseph disease (MJD), are characterized by mutant proteins that generate large nuclear inclusions in neuronal cells. While these inclusions could be pathogenic, beneficial or incidental, it is clear that various nuclear domains differentially associate with specific types of inclusions. In particular, one nuclear domain known as the Cajal body has been shown to associate with inclusions in MJD patient cells. The mutated protein in MJD is ataxin-3. Since the Cajal body plays a role in making the machinery needed to properly process RNA, it is suspected that Cajal body function may be impaired in MJD. Preliminary data support this suspicion. In this application, we will examine if Cajal body activity is altered in neuronal-like cell lines that can express normal and mutant forms of ataxin-3. By fully understanding the mechanisms by which neuronal cells die in certain neurodegenerative disorders, advances can be made in the development of treatments.