Soluble Androgen Receptor Oligomers Underlie Pathology in a Mouse Model of Spinobulbar Muscular Atrophy

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 biochem...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-02, Vol.282 (5), p.3157-3164
Main Authors: Li, Mei, Chevalier-Larsen, Erica S., Merry, Diane E., Diamond, Marc I.
Format: Article
Language:English
Subjects:
Aging
Animals
Disease Models, Animal
Disease Progression
Female
Male
Mice
Muscular Disorders, Atrophic - pathology
Muscular Disorders, Atrophic - physiopathology
Peptide Fragments - analysis
Receptors, Androgen - chemistry
Receptors, Androgen - physiology
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M609972200