Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy

Mei Li, Erica S. Chevalier-Larsen, Diane E. Merry, Marc I. Diamond

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3157-3164
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number5
DOIs
StatePublished - Jan 2 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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