Abstract
Spinal and bulbar muscular atrophy (SBMA) is caused by expression of a polyglutamine (polyQ)-expanded androgen receptor (AR). The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28γ (also referred to as REGγ) is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28α, PA28β) counterparts. To clarify the role of REGγ in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA. Overexpression of REGγ in a PC12 cell model of SBMA increased polyQ-expanded AR aggregation and contributed to polyQ-expanded AR toxicity in the presence of dihydrotestosterone (DHT). These effects of REGγ were independent of its association with the proteasome and may be due, in part, to the decreased binding of polyQ-expanded AR by the E3 ubiquitin-ligase MDM2. Unlike its effects in PC12 cells, REGγ overexpression rescued transgenic SBMA motor neurons from DHT-induced toxicity in a proteasome binding-dependent manner, suggesting that the degradation of a specific 11S proteasome substrate or substrates promotes motor neuron viability. One potential substrate that we found to play a role in mutant AR toxicity is the splicing factor SC35. These studies reveal that, depending on the cellular context, two biological roles for REGγ impact cell viability in the face of polyQ-expanded AR; a proteasome binding-independent mechanism directly promotes mutant AR aggregation while a proteasome binding-dependent mechanism promotes cell viability. The balance between these functions likely determines REGγ effects on polyQ-expanded AR-expressing cells.
Highlights
Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease that is caused by expansion of a polyglutamine-encoding CAG repeat in exon 1 of the androgen receptor (AR) gene (La Spada et al, 1991)
Numerous studies have demonstrated that components of the Ubiquitin-proteasome system (UPS) system are present within nuclear inclusions in cell and animal models of SBMA and tissue of affected SBMA patients (Li et al, 1998; Stenoien et al, 1999; Abel et al, 2001; Walcott and Merry, 2002); we wished to determine whether REGγ co-localizes with hormone-induced ARQ112 nuclear inclusions in this cell model of SBMA
In SBMA, in particular, in which the site of pathogenesis is the nucleus (Takeyama et al, 2002; Montie et al, 2009; Nedelsky et al, 2010), identifying the role of nuclear proteases in the inefficient degradation and aggregation of the mutant AR may be critical to understanding the disease process
Summary
Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease that is caused by expansion of a polyglutamine (polyQ)-encoding CAG repeat in exon 1 of the androgen receptor (AR) gene (La Spada et al, 1991). As in REGγ in SBMA other polyQ diseases, remaining motor neurons are marked by the presence of neuronal intranuclear inclusions (NII) of the mutant polyQ-expanded protein (Li et al, 1998). Proteins that are not exported to the cytoplasm for degradation must be degraded by nuclear proteasomes This difference may explain the requirement for AR nuclear localization in its toxicity, as inhibition of autophagy in cells expressing cytoplasmically localized mutant AR removes the protection that this localization otherwise affords (Montie and Merry, 2009; Montie et al, 2009).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
