The 11S proteasomal activator REGγ Impacts polyglutamine-expanded androgen receptor aggregation and toxicity in cell models of spinal and bulbar muscular atrophy

2011 2011

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Abstract (summary)

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.

Indexing (details)

Cellular biology
0317: Neurosciences
0379: Cellular biology
Identifier / keyword
Biological sciences; Androgen receptor; Muscular atrophy; Neurodegeneration; Polyglutamine; Proteasome
The 11S proteasomal activator REGγ Impacts polyglutamine-expanded androgen receptor aggregation and toxicity in cell models of spinal and bulbar muscular atrophy
Yersak, Jill M.
Number of pages
Publication year
Degree date
School code
DAI-B 72/06, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Merry, Diane E.
Committee member
Eisenlohr, Laurence C.; Grunwald, Gerald B.; Wedegaertner, Philip B.
Thomas Jefferson University
Cell and Developmental Biology
University location
United States -- Pennsylvania
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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