title: Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sahashi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, ka2no@med.nagoya-u.ac.jp sobueg@med.nagoya-u.ac.jp.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92008, USA and.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: Department of Neurology, University of Occupational and Environmental Health School of Medicine, Kitakyushu 807-8555, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Naohide
authors.initials: N
authors.lastname: Kondo
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakatsuji
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Tohnai
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Iida
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92008, USA and.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan, ka2no@med.nagoya-u.ac.jp sobueg@med.nagoya-u.ac.jp.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000818:Animals; D018450:Disease Progression; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons; D018482:Muscle, Skeletal / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009154:Mutation; D009469:Neuromuscular Junction / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D011944:Receptors, Androgen / Q000235:genetics*
chemical_list: C000607144:AR protein, mouse; D016376:Oligonucleotides, Antisense; D011944:Receptors, Androgen