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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.

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Date
2014
Authors
Cortes, Constanza J
La Spada, Albert R
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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 article
Subject
Amyotrophic lateral sclerosis
androgen receptor
antisense oligonucleotide
motor neuron
neurodegeneration
polyglutamine
skeletal muscle
spinal and bulbar muscular atrophy
transgenic mice
Permalink
https://hdl.handle.net/10161/16039
Published Version (Please cite this version)
10.4161/2167549X.2014.962402
Publication 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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Scholars@Duke

Cortes

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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