Disrupted Transforming Growth Factor-beta Signaling in Spinal and Bulbar Muscular Atrophy

作者：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

来源：Journal of Neuroscience, 2010, 30(16): 5702-5712.

DOI：10.1523/JNEUROSCI.0388-10.2010

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 (T beta RII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of T beta RII 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 T beta RII is associated with polyglutamine-induced motor neuron damage in SBMA.

• 出版日期2010-4-21