Elucidation of cellular signaling defect and mechanism of cell-specific degeneration in polyglutamine diseases

脊髓延髓肌萎缩症（SBMA）是一种迟发性下运动神经元疾病，由雄激素受体（AR）中的三核苷酸CAG重复序列扩增引起。虽然人们普遍认为致病性多聚谷氨酰胺蛋白诱导转录失调，下游分子事件仍然难以捉摸。在这里，我们研究了TGF-β信号转导是否在SBMA中失调。在携带突变型人AR的雄性转基因小鼠的脊髓运动神经元中，磷酸化Smad 2/3的核转位受到抑制。致病性AR通过与NF-Y和p300/CBP相关因子（P/CAF）的异常相互作用抑制TGF-β受体II（TβRII）的转录。此外，TβRII的过表达减弱了致病性AR的细胞毒性。因此，本研究表明，由于TβRII转录失调导致的TGF-β破坏与多聚谷氨酰胺诱导的SBMA运动神经元损伤有关。

Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins induce transcriptional dysregulation, the down-stream molecular events have remained elusive. Here we examined whether TGF-βsignaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3 is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. The pathogenic AR inhibits the transcription of TGF-βreceptor type II (TβRII), via abnormal interactions with NF-Y and p300/CBP-associated factor (P/CAF). Furthermore, overexpression of TβRII dampens the cytotoxicity of the pathogenic AR. The present study thus indicates that disruption of TGF-βdue to the transcriptional dysregulation of TβRII is associated with polyglutamine-induced motor neuron damage in SBMA.