title: Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.
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.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Constanza J
authors.initials: CJ
authors.lastname: Cortes
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Taiji
authors.initials: T
authors.lastname: Tsunemi
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Ly
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Seiya
authors.initials: S
authors.lastname: Tokunaga
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Lopez
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: 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.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: 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.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009069:Movement Disorders / Q000209:etiology / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine
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