The 11S proteasomal activator REGγ Impacts polyglutamine-expanded androgen receptor aggregation and toxicity in cell models of spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease that is caused by an expanded CAG repeat, which encodes a polyglutamine tract in the amino-terminal region of the androgen receptor (AR). Substantial data have illuminated the importance of the nucleus in SBMA pathogenesis; the expanded polyglutamine (polyQ) androgen receptor must reside in the nucleus, in the presence of ligand, in order to cause disease. Evidence that nuclear proteasomes inefficiently clear polyQ-expanded AR includes the finding that neuronal nuclear inclusions (NII), the pathological hallmark of SBMA, contain the amino-terminal portion of the AR, molecular chaperones, and components of the ubiquitin proteasome system (UPS). Here, we focus on how the nuclear 11S-proteasomal activator REGγ impacts polyQ-expanded AR metabolism. We reveal that REGã assumes either a proteasome binding-dependent or -independent role in the nucleus, depending on the cellular context. REGγ overexpression in a SBMA PC12 cell model increased polyQ-expanded AR aggregation and failed to protect cells from hormone-dependent toxicity through a proteasome binding-independent mechanism. Moreover, REGγ overexpression decreased polyQ-expanded AR polyubiquitylation and interaction with the E3 ligase MDM2. Preliminary genetic studies demonstrated that MDM2 overexpression may counter the REGγ aggregation effect, suggesting that REGγ acts as a competitor of the E3 ligase MDM2, influencing polyQ-expanded AR aggregation through its inhibition of AR polyubiquitylation and degradation. Conversely, we found that REGγ functions through its 11S-proteasomal activator role to rescue SBMA motor neurons from hormone-induced toxicity. How this direct proteasomal role works to protect SBMA motor neurons is currently unknown. Thus, our studies establish two biological roles of REGγ in impacting polyQ-expanded AR metabolism; exploration of the REGγ 11S-activator role may uncover novel targets for therapeutic advancement.
0379: Cellular biology