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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-\u03b2 signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2\/3, a key step in TGF-\u03b2 signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human<jats:italic>AR<\/jats:italic>. 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-\u03b2 receptor type II (T\u03b2RII) via abnormal interactions with NF-Y and p300\/CBP-associated factor. Furthermore, overexpression of T\u03b2RII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-\u03b2 due to the transcriptional dysregulation of T\u03b2RII is associated with polyglutamine-induced motor neuron damage in SBMA.<\/jats:p>","DOI":"10.1523\/jneurosci.0388-10.2010","type":"journal-article","created":{"date-parts":[[2010,4,21]],"date-time":"2010-04-21T17:08:39Z","timestamp":1271869719000},"page":"5702-5712","source":"Crossref","is-referenced-by-count":78,"title":["Disrupted Transforming Growth Factor-\u03b2 Signaling in Spinal and Bulbar Muscular 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