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.

Cortes, Constanza J; La Spada, Albert R

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.

dc.contributor.author	Cortes, Constanza J
dc.contributor.author	La Spada, Albert R
dc.coverage.spatial	United States
dc.date.accessioned	2018-02-01T15:06:16Z
dc.date.available	2018-02-01T15:06:16Z
dc.date.issued	2014
dc.description.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.
dc.identifier	https://www.ncbi.nlm.nih.gov/pubmed/26942099
dc.identifier	962402
dc.identifier.issn	2167-5511
dc.identifier.uri	https://hdl.handle.net/10161/16039
dc.language	eng
dc.publisher	Informa UK Limited
dc.relation.ispartof	Rare Dis
dc.relation.isversionof	10.4161/2167549X.2014.962402
dc.subject	Amyotrophic lateral sclerosis
dc.subject	androgen receptor
dc.subject	antisense oligonucleotide
dc.subject	motor neuron
dc.subject	neurodegeneration
dc.subject	polyglutamine
dc.subject	skeletal muscle
dc.subject	spinal and bulbar muscular atrophy
dc.subject	transgenic mice
dc.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.
dc.type	Journal article
duke.contributor.orcid	Cortes, Constanza J\|0000-0002-6033-7428
pubs.author-url	https://www.ncbi.nlm.nih.gov/pubmed/26942099
pubs.begin-page	e962402
pubs.issue	1
pubs.organisational-group	Clinical Science Departments
pubs.organisational-group	Duke
pubs.organisational-group	Duke Institute for Brain Sciences
pubs.organisational-group	Institutes and Provost's Academic Units
pubs.organisational-group	Neurology
pubs.organisational-group	Neurology, Behavioral Neurology
pubs.organisational-group	School of Medicine
pubs.organisational-group	University Institutes and Centers
pubs.publication-status	Published online
pubs.volume	2

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