The nature of the nuclear events that transform the mutant androgen receptor (AR) into a toxic species have become a major focus of study in the field of spinal and bulbar muscular atrophy (SBMA) research following the discovery that the onset and progression of disease are hormone-dependent. It is unknown at what point in its metabolism the mutant AR becomes toxic to motor neurons, although work from our lab and others has begun to dissect the pathological pathway. We have recently determined that nuclear localization of the polyglutamine-expanded AR is essential, but not sufficient for disease. Therefore, hormone-dependent nuclear metabolism of the mutant AR, including post-translational modification, protein-protein interactions, degradation and cleavage are critical points of interest in determining the events that lead to its toxicity. One post-translational modification of interest is acetylation. Known AR acetylation sites are clustered in the KLKK motif located in the hinge region at positions 630/632/633. Our preliminary studies have revealed that acetylation of these lysine residues is required for both the aggregation and toxicity of polyglutamine-expanded AR in cell models. We propose in this application to determine the role of AR acetylation at these sites in vivo, through the creation of transgenic mice that express a polyglutamine-expanded AR that is incapable of acetylation at these sites. Through the characterization of motor function, as well as neuropathological and biochemical features in these transgenic mice, we will determine whether acetylation of the AR at amino acids 630/632/633 is required for disease features in vivo. We expect that the results from these studies will allow us to determine whether acetylation of the mutant AR represents a valid drug target for further therapeutic development in SBMA.
Spinal and bulbar muscular atrophy (SBMA) is one of 9 polyglutamine diseases, which are themselves part of a large family of neurodegenerative diseases characterized by protein misfolding and accumulation;these diseases also include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). We have identified a therapeutic target in SBMA that involves the acetylation of the mutant androgen receptor protein. The studies proposed here will determine the role for this modification in a mouse model of SBMA;the validation of a role for acetylation in SBMA will open new and powerful opportunities for therapeutic development.
