Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 88, Issue 10, Pages 2207-2216Publisher
WILEY
DOI: 10.1002/jnr.22389
Keywords
polyglutamine disease; SBMA; androgen receptor; B2; inclusions
Categories
Funding
- NINDS-NIH
- Kennedy's Disease Association
- Muscular Dystrophy Association
- NIH [NS053825]
Ask authors/readers for more resources
Expanded polyglutamine tracts cause neurodegeneration through a toxic gain-of-function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a defensive response of the cell to the presence of unfolded protein. Recently, the compound B2 has been shown to increase inclusion formation and decrease toxicity of polyglutamine-expanded huntingtin in cultured cells. We explored the effect of B2 on spinal and bulbar muscular atrophy (SBMA). SBMA is caused by expansion of polyglutamine in the androgen receptor (AR) and is characterized by the loss of motor neurons in the brain-stem and spinal cord. We found that B2 increases the deposition of mutant AR into nuclear inclusions, without altering the ligand-induced aggregation, expression, or subcellular distribution of the mutant protein. The effect of B2 on inclusions was associated with a decrease in AR transactivation function. We show that B2 reduces mutant AR toxicity in cell and fly models of SBMA, further supporting the idea that accumulation of polyglutamine-expanded protein into inclusions is protective. Our findings suggest B2 as a novel approach to therapy for SBMA. (C) 2010 Wiley-Liss, inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available