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B2 attenuates polyglutamine‐expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy
Author(s) -
Palazzolo Isabella,
Nedelsky Natalia B.,
Askew Caitlin E.,
Harmison George G.,
Kasantsev Aleksey G.,
Taylor J. Paul,
Fischbeck Kenneth H.,
Pennuto Maria
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22389
Subject(s) - spinal and bulbar muscular atrophy , androgen receptor , neurodegeneration , atrophy , transactivation , biology , microbiology and biotechnology , mutant , inclusion bodies , medicine , endocrinology , chemistry , genetics , gene expression , prostate cancer , disease , cancer , escherichia coli , gene
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 brainstem 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. © 2010 Wiley‐Liss, Inc.