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Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.


ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

SUBMITTER: Lieberman AP 

PROVIDER: S-EPMC4356525 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.

Lieberman Andrew P AP   Yu Zhigang Z   Murray Sue S   Peralta Raechel R   Low Audrey A   Guo Shuling S   Yu Xing Xian XX   Cortes Constanza J CJ   Bennett C Frank CF   Monia Brett P BP   La Spada Albert R AR   Hung Gene G  

Cell reports 20140416 3


Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent we  ...[more]

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