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Neuron. 2014 Apr 16;82(2):295-307. doi: 10.1016/j.neuron.2014.03.001.

Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

Author information

1
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
4
Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
5
Department of Neurology, University of Washington, Seattle, WA 98195, USA.
6
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
7
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: alaspada@ucsd.edu.

Abstract

X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments.

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PMID:
24742458
PMCID:
PMC4096235
DOI:
10.1016/j.neuron.2014.03.001
[Indexed for MEDLINE]
Free PMC Article

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