title: Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA.
abstract: Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by a polyglutamine expansion in the androgen receptor (AR) and is associated with misfolding and aggregation of the mutant AR. We investigated the role of an interdomain interaction between the amino (N)-terminal FxxLF motif and carboxyl (C)-terminal AF-2 domain in a mouse model of SBMA. Male transgenic mice expressing polyQ-expanded AR with a mutation in the FxxLF motif (F23A) to prevent the N/C interaction displayed substantially improved motor function compared with N/C-intact AR-expressing mice and showed reduced pathological features of SBMA. Serine 16 phosphorylation was substantially enhanced by the F23A mutation; moreover, the protective effect of AR F23A was dependent on this phosphorylation. These results reveal an important role for the N/C interaction on disease onset in mice and suggest that targeting AR conformation could be a therapeutic strategy for patients with SBMA.
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Zboray
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pluciennik
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Curtis
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Berman-Booty
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Orr
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Center for Cell Signaling, Charlottesville, VA 22908, USA.
authors.forename: Cristina T
authors.initials: CT
authors.lastname: Kesler
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Berger
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gioeli
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Center for Cell Signaling, Charlottesville, VA 22908, USA.
authors.forename: Bryce M
authors.initials: BM
authors.lastname: Paschal
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: diane.merry@jefferson.edu.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Merry
mesh_terms: D000818:Animals; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000503:physiopathology*; D004195:Disease Models, Animal; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen