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

Masahisa Katsuno, Hiroaki Adachi, Makoto Minamiyama, Masahiro Waza, Hideki Doi, Naohide Kondo, Hiroyuki Mizoguchi, Atsumi Nitta, Kiyofumi Yamada, Haruhiko Banno, Keisuke Suzuki, Fumiaki Tanaka, Gen Sobue

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)5702-5712
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number16
DOIs
Publication statusPublished - 21-04-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience

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