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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA.
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SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA.

机译：SIRT1通过SBMA细胞模型中雄激素受体的去乙酰化作用来调节聚集和毒性。

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摘要

Posttranslational protein modifications can play a major role in disease pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity of a variety of proteotoxic proteins. The androgen receptor (AR) is substantially modified, in response to hormone binding, by phosphorylation, sumoylation, and acetylation; these modifications might thus contribute to DHT-dependent polyglutamine (polyQ)-expanded AR proteotoxicity in spinal and bulbar muscular atrophy (SBMA). SIRT1, a nuclear protein and deacetylase of the AR, is neuroprotective in many neurodegenerative disease models. Our studies reveal that SIRT1 also offers protection against polyQ-expanded AR by deacetylating the AR at lysines 630/632/633. This finding suggested that nuclear AR acetylation plays a role in the aberrant metabolism and toxicity of polyQ-expanded AR. Subsequent studies revealed that the polyQ-expanded AR is hyperacetylated and that pharmacologic reduction of acetylation reduces mutant AR aggregation. Moreover, genetic mutation to inhibit polyQ-expanded AR acetylation of lysines 630/632/633 substantially decreased its aggregation and completely abrogated its toxicity in cell lines and motor neurons. Our studies also reveal one means by which the AR acetylation state likely modifies polyQ-expanded AR metabolism and toxicity, through its effect on DHT-dependent AR stabilization. Overall, our findings reveal a neuroprotective function of SIRT1 that operates through its deacetylation of polyQ-expanded AR and highlight the potential of both SIRT1 and AR acetylation as powerful therapeutic targets in SBMA.
机译：翻译后蛋白质修饰可在疾病发病机理中发挥重要作用;磷酸化，磺酰化和乙酰化可调节多种蛋白毒性蛋白的毒性。响应激素结合，雄激素受体（AR）通过磷酸化，磺酰化和乙酰化得到显着修饰。因此，这些修饰可能有助于DHT依赖的聚谷氨酰胺（polyQ）扩大脊髓和延髓性肌萎缩症（SBMA）中的AR蛋白毒性。 SIRT1是AR的核蛋白和脱乙酰基酶，在许多神经退行性疾病模型中具有神经保护作用。我们的研究表明，SIRT1还通过在630/632/633赖氨酸上使AR脱乙酰化，从而提供针对polyQ扩增AR的保护。该发现表明核AR的乙酰化在polyQ-扩增的AR的异常代谢和毒性中起作用。随后的研究表明，polyQ扩增的AR被高度乙酰化，药理学上乙酰化的降低降低了突变体AR的聚集。此外，抑制赖氨酸630/632/633的polyQ扩增的AR乙酰化的基因突变大大降低了其聚集，并完全消除了其在细胞系和运动神经元中的毒性。我们的研究还揭示了AR乙酰化状态可能通过其对DHT依赖的AR稳定作用的作用来修饰polyQ扩展的AR代谢和毒性的一种方法。总体而言，我们的发现揭示了SIRT1的神经保护功能，该功能通过其对polyQ扩增的AR的脱乙酰作用而发挥作用，并突出了SIRT1和AR乙酰化作为SBMA中强大的治疗靶标的潜力。

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