Polyglutamine Neurotoxicity in SBMA
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease affecting motor neurons of the anterior horn and brainstem and caused by the expansion of a polyglutamine tract within the androgen receptor (AR). Recent findings have shown that the disease is initiated by the binding of the AR to its androgenic ligand, with its subsequent translocation to the nucleus. Within the nucleus, the mutant AR likely functions properly to activate the transcription of target genes;however, fragments of the amino- terminus of the AR accumulate within the nucleus. Substantial evidence indicates that the polyglutamine expansion results in disease, in part, due to its impact on the turnover of the mutant AR. The long-term goals of this proposal are to understand the molecular basis for the inefficient degradation of the expanded polyglutamine AR through the characterization of candidate proteasomal regulators and through a structure/function analysis of AR domains and post-translational modifications . We hypothesize that the normal trafficking and post-translational modifications of the AR are impacted by polyglutamine expansion. Understanding the role of these domains in AR degradative processes and in disease pathogenesis will provide new targets for therapeutic development. Polyglutamine diseases represent a larger family of neurodegenerative diseases characterized by protein misfolding and accumulation;these diseases include Alzheimer's disease, Huntington disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). The research proposed here should lead to a better understanding of the specific pathogenic mechanisms responsible for SBMA;these studies should lead, as well, to a better understanding of these other protein accumulation diseases.