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 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.
Katsuno
Masahisa
M
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. ka2no@med.nagoya-u.ac.jp
Adachi
Hiroaki
H
Minamiyama
Makoto
M
Waza
Masahiro
M
Doi
Hideki
H
Kondo
Naohide
N
Mizoguchi
Hiroyuki
H
Nitta
Atsumi
A
Yamada
Kiyofumi
K
Banno
Haruhiko
H
Suzuki
Keisuke
K
Tanaka
Fumiaki
F
Sobue
Gen
G
D000368:Aged; D000818:Animals; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology
D016212:Transforming Growth Factor beta
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