Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and...

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Bibliographic Details
Published in:The Journal of neuroscience 2010-04, Vol.30 (16), p.5702-5712
Main Authors: Katsuno, Masahisa, Adachi, Hiroaki, Minamiyama, Makoto, Waza, Masahiro, Doi, Hideki, Kondo, Naohide, Mizoguchi, Hiroyuki, Nitta, Atsumi, Yamada, Kiyofumi, Banno, Haruhiko, Suzuki, Keisuke, Tanaka, Fumiaki, Sobue, Gen
Format: Article
Language:English
Subjects:
Aged
Animals
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Motor Neurons - metabolism
Motor Neurons - pathology
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - metabolism
Muscular Atrophy, Spinal - pathology
Muscular Disorders, Atrophic - genetics
Muscular Disorders, Atrophic - metabolism
Muscular Disorders, Atrophic - pathology
Nerve Degeneration - genetics
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Signal Transduction - physiology
Transforming Growth Factor beta - antagonists & inhibitors
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - physiology
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Summary:Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-beta signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-beta signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-beta receptor type II (TbetaRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TbetaRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-beta due to the transcriptional dysregulation of TbetaRII is associated with polyglutamine-induced motor neuron damage in SBMA.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0388-10.2010