The role of VCP in the pathogenesis of Kennedy's disease
Summary: Spinal and Bulbar Muscular Atrophy (SBMA; Kennedy’s Disease) is a neuromuscular disease that affects motor neurons and skeletal muscles. The symptoms of SBMA include progressive weakness of the limbs and facial muscles, as well as difficulty with speaking and swallowing. SBMA is an X-linked disease that primarily affects men, and is caused by a polyglutamine expansion in the gene Androgen Receptor (AR). The polyglutamine expansion in AR makes the protein toxic, and can lead to the formation of protein aggregates inside of cells as well as cell death. SBMA is one of nine different polyglutamine expansion disorders that are linked to neurodegeneration. How polyglutamine expanded AR causes SBMA is still being studied, and there are no effective therapeutics available. In order to better understand the mechanisms that cause SBMA and translate these results into the development of effective therapeutics, my proposal aims to assess how the protein Valosin-Containing Protein (VCP) is involved in SBMA. VCP plays a role in breaking down mutant or damaged proteins, and has been studied in other neurodegenerative disorders. Based on our preliminary data, we hypothesize that VCP can regulate the expression and/or the activity of polyglutamine expanded AR. Our proposal will examine how VCP affects the development of protein aggregates and cell death in SBMA. We will use cell culture models and fruit flies, both of which are commonly used to study SBMA. This research will help develop a more thorough understanding of what causes SBMA, and provide important information when developing new therapeutics for this devastating disease.
