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Abstract：
Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG trinucleotide repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite outgrowth, induced neurite retraction, and inhibited neurite regrowth. This dysfunction was independent of polyQ-expanded AR transcriptional activity at androgen response elements (ARE). We further showed that the formation of polyQ-expanded AR intranuclear inclusions promoted neurite retraction, which coincided with reduced expression of the neuronal differentiation marker β-III-Tubulin. Finally, we revealed that cell death is not the primary outcome for cells undergoing neurite retraction; rather, these cells become senescent. Our findings reveal that mechanisms independent of AR canonical transcriptional activity underly neurite defects in a cell model of SBMA and identify senescence as a pathway implicated in this pathology. These findings suggest that in the absence of a role for AR canonical transcriptional activity in the SBMA pathologies described here, the development of SBMA therapeutics that preserve this activity may be desirable. This approach may be broadly applicable to other polyglutamine diseases such as Huntington\'s disease and spinocerebellar ataxias.
摘要：
脊髓和延髓性肌萎缩症（SBMA）是由雄激素受体（AR）基因中编码多聚谷氨酰胺（polyQ）的CAG三核苷酸重复扩增引起的缓慢进展的神经肌肉疾病，导致AR聚集，下运动神经元死亡，肌肉萎缩.AR是一种配体激活的转录因子，可调节神经元结构并促进轴突再生；然而，AR转录功能是否有助于疾病的发病机制尚不完全清楚。使用SBMA的分化PC12细胞模型，我们确定了polyQ扩增的AR在调节神经突生长和维持方面的功能障碍。具体来说,我们发现在雄激素存在的情况下,polyQ扩展的AR抑制神经突生长，诱导神经突缩回，并抑制神经突再生。这种功能障碍与雄激素反应元件（ARE）的polyQ扩增的AR转录活性无关。我们进一步表明，polyQ扩增的AR核内包涵体的形成促进神经突回缩，这与神经元分化标记β-III-微管蛋白的表达降低相吻合。最后,我们发现，细胞死亡不是神经突退缩细胞的主要结果；相反，这些细胞变得衰老。我们的发现表明，与AR规范转录活性无关的机制在SBMA细胞模型中隐藏了神经突缺陷，并将衰老确定为与该病理学有关的途径。这些发现表明，在这里描述的SBMA病理中缺乏AR规范转录活性的作用，可能需要开发保留该活性的SBMA治疗剂。这种方法可能广泛适用于其他多谷氨酰胺疾病，例如亨廷顿氏病和脊髓小脑共济失调。
