Abstract/Details

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)


Subject
Neurosciences;
Cellular biology
Classification
0317: Neurosciences
0379: Cellular biology
Identifier / keyword
Biological sciences, Androgen receptor, Muscular atrophy, Neurodegeneration, Polyglutamine, Proteasome
Title
The 11S proteasomal activator REGγ Impacts polyglutamine-expanded androgen receptor aggregation and toxicity in cell models of spinal and bulbar muscular atrophy
Author
Yersak, Jill M.
Number of pages
230
Publication year
2011
Degree date
2011
School code
0272
Source
DAI-B 72/06, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124543178
Advisor
Merry, Diane E.
Committee member
Eisenlohr, Laurence C.; Grunwald, Gerald B.; Wedegaertner, Philip B.
University/institution
Thomas Jefferson University
Department
Cell and Developmental Biology
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3445258
ProQuest document ID
861483982
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/861483982
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