Sunday, May 18, 2025
5/18/2025
The role of the AR interactome in SBMA - Project Summary: Several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, as well as the polyglutamine expansion diseases, result from protein misfolding and accumulation due to genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington’s disease and several spinocerebellar ataxias. Although the precise pathways leading to neuronal dysfunction and death are unknown, the evaluation of mouse and cell models of these diseases has yielded mechanistic insights into disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. The cell and mouse models of SBMA used within this proposal reproduce the androgen- and polyglutamine- dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Our long-term objectives are to use these models to develop a mechanistic understanding of hormone-dependent, polyglutamine-expanded AR toxicity. A growing body of evidence suggests that long polyQ tracts cause cellular dysfunction and ultimately cell death, at least in part by dysregulating protein-protein interactions that sustain normal cellular function. We have utilized multiple quantitative proteomics approaches to identify changes in AR protein interaction networks caused by polyQ expansion in a cell model, and in the previous funding period, we established an important role for one of these interacting proteins, USP7, in SBMA pathogenesis, validating this approach to understand disease mechanisms. We propose here to 1) carry out additional interactome screens in SBMA cell models and in spinal cord and muscle tissues of a validated mouse model of SBMA and begin the investigation into the roles of these differentially interacting proteins, 2) continue our mechanistic studies of the role of USP7, and of other differential interactors, in SBMA, and 3) develop a novel therapeutic approach to specifically target the USP7-AR interaction in SBMA. We anticipate that results from these studies will lead us to a deeper understanding of the molecular pathogenesis of SBMA, and will yield novel pathways amenable to therapeutic modulation for SBMA.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).