TY - JOUR
T1 - Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy
AU - Li, Mei
AU - Chevalier-Larsen, Erica S.
AU - Merry, Diane E.
AU - Diamond, Marc I.
PY - 2007/1/2
Y1 - 2007/1/2
N2 - In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of the protein is an insoluble or soluble aggregate or a monomer. We have addressed this question by studying a full-length androgen receptor (AR) mouse model of SBMA. We used biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single ∼50-kDa N-terminal polyglutamine-containing AR fragment. AR oligomers appeared several weeks prior to symptom onset, were distinct and temporally dissociated from intranuclear inclusions, and disappeared rapidly after castration, which halts disease. This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA.
AB - In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of the protein is an insoluble or soluble aggregate or a monomer. We have addressed this question by studying a full-length androgen receptor (AR) mouse model of SBMA. We used biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single ∼50-kDa N-terminal polyglutamine-containing AR fragment. AR oligomers appeared several weeks prior to symptom onset, were distinct and temporally dissociated from intranuclear inclusions, and disappeared rapidly after castration, which halts disease. This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA.
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U2 - 10.1074/jbc.M609972200
DO - 10.1074/jbc.M609972200
M3 - Article
C2 - 17121819
AN - SCOPUS:34047269594
SN - 0021-9258
VL - 282
SP - 3157
EP - 3164
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
ER -