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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lieberman, AP; Yu, Z; Murray, S; Peralta, R; Low, A; Guo, S; Yu, XX; Cortes, CJ; Bennett, CF; Monia, BP; La Spada, AR; Hung, G

Published Date

  • May 2014

Published In

Volume / Issue

  • 7 / 3

Start / End Page

  • 774 - 784

PubMed ID

  • 24746732

Pubmed Central ID

  • 24746732

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

International Standard Serial Number (ISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2014.02.008

Language

  • eng