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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.

SUBMITTER: Zboray L 

PROVIDER: S-EPMC4684905 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA.

Zboray Lori L   Pluciennik Anna A   Curtis Dana D   Liu Yuhong Y   Berman-Booty Lisa D LD   Orr Christopher C   Kesler Cristina T CT   Berger Tamar T   Gioeli Daniel D   Paschal Bryce M BM   Merry Diane E DE  

Cell reports 20151207 10


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 displaye  ...[more]

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