Lori Zboray1, Anna Pluciennik1, Dana Curtis1, Yuhong Liu1, Lisa D Berman-Booty2, Christopher Orr1, Cristina T Kesler3, Tamar Berger1, Daniel Gioeli4, Bryce M Paschal3, Diane E Merry5. 1. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. 2. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. 3. Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Center for Cell Signaling, Charlottesville, VA 22908, USA. 4. Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA. 5. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: diane.merry@jefferson.edu.
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.
Spinal and bulbar muscular atrophy (n class="Gene">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 ARF23A 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.
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