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Cited by 169Genetic Neurodegenerative DiseasesAmyotrophic Lateral Sclerosis ResearchNeurogenetic and Muscular Disorders Research

Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

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Lieberman, Andrew P., Yu, Zhigang, Murray, Sue, Peralta, Raechel, Low, Audrey, Guo, Shuling, Yu, Xing Xian, Cortes, Constanza J. +4 more·2014·Cell Reports
DOI 10.1016/j.celrep.2014.02.008PMC PMC4356525
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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.

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  • ASOs can specifically alter levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself.

    “Due to the precision afforded by complementary binding of an ASO to its target transcript of interest, ASOs have emerged as an invaluable tool in specifically altering levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself (38, 51–54).”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [38]

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Cited by

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Authors
Lieberman, A. P., Yu, Z., Murray, S., Peralta, R., Low, A., Guo, S., Yu, X. X., Cortes, C. J., Bennett, C. F., Monia, B. P., La Spada, A. R., & Hung, G.
Affiliations
  • University of Michigan (US)
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
  • Lieberman, Andrew P.
  • Hung, Gene
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2014-05
Volume
7
Issue
3
Pages
774-784
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2014.02.008
PMC
PMC4356525
OpenAlex
W2050679356
Cited by
169
References
3
Citations by year
2026: 5 · 2025: 11 · 2024: 6 · 2023: 11 · 2022: 12 · 2021: 6 · 2020: 18 · 2019: 21 · 2018: 16 · 2017: 16 · 2016: 12 · 2015: 23 · 2014: 12
FWCI
9.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (R01NS055746, R01NS041648)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Keywords
spinal and bulbar muscular atrophy, androgen receptor, polyglutamine, antisense oligonucleotides, muscle atrophy, motor neuronopathy, BAC transgenic mice, lifespan extension, muscle gene expression, grip strength, subcutaneous drug delivery
MeSH terms
Animals, Body Weight, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Receptors, Androgen, Testosterone, Survival Rate, Oligonucleotides, Antisense, Muscle, Skeletal, Muscle Fibers, Skeletal, Hand Strength, Muscular Disorders, Atrophic, Mice, Gene Knock-In Techniques, Transcriptome

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