RT Journal Article SR Electronic T1 Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 5702 OP 5712 DO 10.1523/JNEUROSCI.0388-10.2010 VO 30 IS 16 A1 Masahisa Katsuno A1 Hiroaki Adachi A1 Makoto Minamiyama A1 Masahiro Waza A1 Hideki Doi A1 Naohide Kondo A1 Hiroyuki Mizoguchi A1 Atsumi Nitta A1 Kiyofumi Yamada A1 Haruhiko Banno A1 Keisuke Suzuki A1 Fumiaki Tanaka A1 Gen Sobue YR 2010 UL http://www.jneurosci.org/content/30/16/5702.abstract 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.