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 biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single approximately 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.
Li
Mei
M
Department of Neurology, Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), California 94143, USA.
Chevalier-Larsen
Erica S
ES
Merry
Diane E
DE
Diamond
Marc I
MI
D000375:Aging; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D008297:Male; D051379:Mice; D020966:Muscular Disorders, Atrophic / Q000473:pathology / Q000503:physiopathology*; D010446:Peptide Fragments / Q000032:analysis; D011944:Receptors, Androgen / Q000737:chemistry* / Q000502:physiology*
D010446:Peptide Fragments; D011944:Receptors, Androgen