RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Cortes, Constanza J  La Spada, Albert R 
Citation: Cortes CJ and La Spada AR, Rare Dis. 2014 Oct 30;2(1):e962402. doi: 10.4161/2167549X.2014.962402. eCollection 2014.
RGD ID: 11576229
Pubmed: (View Article at PubMed) PMID:26942099
DOI: Full-text: DOI:10.4161/2167549X.2014.962402

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.

Annotation

Disease Annotations    
Kennedy's disease  (IMP,ISO)

Objects Annotated

Genes (Rattus norvegicus)
Ar  (androgen receptor)

Genes (Mus musculus)
Ar  (androgen receptor)

Genes (Homo sapiens)
AR  (androgen receptor)


Additional Information