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

Constanza J Cortes; Shuo-Chien Ling; Ling T Guo; Gene Hung; Taiji Tsunemi; Linda Ly; Seiya Tokunaga; Edith Lopez; Bryce L Sopher; C Frank Bennett; G Diane Shelton; Don W Cleveland; Albert R La Spada

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / metabolism
Age Factors
Animals
Body Weight / genetics
Brain / pathology*
Disease Models, Animal
Disease Progression
Gene Expression Regulation / genetics
Humans
Male
Mice
Mice, Transgenic
Motor Neurons / metabolism
Motor Neurons / pathology
Movement Disorders / etiology
Movement Disorders / genetics
Muscle Strength / genetics
Muscle, Skeletal / metabolism*
Muscle, Skeletal / pathology
Muscular Disorders, Atrophic / complications
Muscular Disorders, Atrophic / genetics*
Muscular Disorders, Atrophic / pathology*
Peptides / genetics*
Phenotype
Receptors, Androgen / genetics*
Receptors, Androgen / metabolism

Substances

Actins
Peptides
Receptors, Androgen
polyglutamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding