TY - JOUR
T1 - Disrupted transforming growth factor-β signaling in spinal and bulbar muscular atrophy
AU - Katsuno, Masahisa
AU - Adachi, Hiroaki
AU - Minamiyama, Makoto
AU - Waza, Masahiro
AU - Doi, Hideki
AU - Kondo, Naohide
AU - Mizoguchi, Hiroyuki
AU - Nitta, Atsumi
AU - Yamada, Kiyofumi
AU - Banno, Haruhiko
AU - Suzuki, Keisuke
AU - Tanaka, Fumiaki
AU - Sobue, Gen
PY - 2010/4/21
Y1 - 2010/4/21
N2 - 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-β signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-β 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-β receptor type II (TβRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TβRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-β due to the transcriptional dysregulation of TβRII is associated with polyglutamine-induced motor neuron damage in SBMA. Copyright
AB - 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-β signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-β 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-β receptor type II (TβRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TβRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-β due to the transcriptional dysregulation of TβRII is associated with polyglutamine-induced motor neuron damage in SBMA. Copyright
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U2 - 10.1523/JNEUROSCI.0388-10.2010
DO - 10.1523/JNEUROSCI.0388-10.2010
M3 - Article
C2 - 20410122
AN - SCOPUS:77951520909
SN - 0270-6474
VL - 30
SP - 5702
EP - 5712
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 16
ER -