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.
Type
Journal articleSubject
Amyotrophic lateral sclerosisandrogen receptor
antisense oligonucleotide
motor neuron
neurodegeneration
polyglutamine
skeletal muscle
spinal and bulbar muscular atrophy
transgenic mice
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https://hdl.handle.net/10161/16039Published Version (Please cite this version)
10.4161/2167549X.2014.962402Publication Info
Cortes, Constanza J; & La Spada, Albert R (2014). 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. Rare Dis, 2(1). pp. e962402. 10.4161/2167549X.2014.962402. Retrieved from https://hdl.handle.net/10161/16039.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Constanza J Cortes
Adjunct Assistant Professor in the Department of Neurology
I am interested in understanding how our brain ages, and in particular, how it ages
as an integrated part of a physiological system. My research represents a cutting
edge approach to our understanding of brain plasticity and aging, as it suggests that
distant tissues such as skeletal muscle may be fundamentally influencing the rate
at which our brain ages. Importantly, as these conversations may be disrupted in age-associated
neurodegenerative diseases (such as Alzheimer's disease), I am

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