Palazzolo Isabella, Stack Conor, Kong Lingling, Musaro Antonio, Adachi Hiroaki, Katsuno Masahisa, Sobue Gen, Taylor J Paul, Sumner Charlotte J, Fischbeck Kenneth H, Pennuto Maria
Neurogenetics Branch, NINDS, NIH, Bethesda, MD 20892, USA.
Neuron. 2009 Aug 13;63(3):316-28. doi: 10.1016/j.neuron.2009.07.019.
Expansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA.
雄激素受体（AR）中聚谷氨酰胺序列的扩展会导致脊髓延髓肌肉萎缩症（SBMA）。我们之前表明，Akt介导的AR磷酸化会降低配体结合能力并减弱突变型AR的毒性。在此，我们表明在培养物中，胰岛素样生长因子1（IGF-1）通过Akt对AR的磷酸化作用，经由泛素-蛋白酶体系统减少AR聚集并增加AR清除。在体内，在骨骼肌中选择性过表达肌肉特异性IGF-1同工型的SBMA转基因小鼠显示出Akt激活增加、AR磷酸化增加以及AR聚集减少的证据。增强IGF-1/Akt信号传导可挽救行为和组织病理学异常、延长寿命，并减轻SBMA小鼠的肌肉和脊髓病变。本研究确立了IGF-1/Akt介导的突变型AR失活作为一种在体内对抗疾病的策略，并证明骨骼肌是SBMA治疗干预的可行靶组织。
