title: Motor neuron degeneration in spinal and Bulbar Muscular Atrophy is a skeletal muscle-driven process: Relevance to therapy development and implications for related motor neuron diseases.
abstract: Non-cell autonomous degeneration has arisen as an important mechanism in neurodegenerative disorders. Using a novel line of BAC androgen receptor (AR) transgenic mice with a floxed transgene (BAC fxAR121), we uncovered a key role for skeletal muscle in X-linked Spinal and Bulbar Muscular Atrophy (SBMA), a motor neuronopathy caused by a polyglutamine expansion in exon 1 of the AR gene. By excising the mutant AR transgene from muscle only, we achieved complete rescue of neuromuscular phenotypes in these mice, despite retaining strong CNS expression. Furthermore, we delivered an antisense oligonucleotide (ASO) directed against the human AR transgene by peripheral injection, and documented that peripheral ASO delivery could rescue muscle weakness and premature death in BAC fxAR121 mice. Our results reveal a crucial role for skeletal muscle in SBMA disease pathogenesis, and offer an appealing avenue for therapy development for SBMA and perhaps also for related motor neuron diseases.
authors.affiliation: Department of Pediatrics; Cellular & Molecular Medicine and Neurosciences; Division of Biological Sciences; Institute for Genomic Medicine; Sanford Consortium for Regenerative Medicine; University of California ; San Diego, CA USA.
authors.forename: Constanza J
authors.initials: CJ
authors.lastname: Cortes
authors.affiliation: Department of Pediatrics; Cellular & Molecular Medicine and Neurosciences; Division of Biological Sciences; Institute for Genomic Medicine; Sanford Consortium for Regenerative Medicine; University of California; San Diego, CA USA; Rady Children's Hospital; San Diego, CA USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
keywords: Amyotrophic lateral sclerosis; androgen receptor; antisense oligonucleotide; motor neuron; neurodegeneration; polyglutamine; skeletal muscle; spinal and bulbar muscular atrophy; transgenic mice