Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease
Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease
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DOI：
10.1093/hmg/ddn273
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Marsh, J. Lawrence
中科院分区：
文献类型：
--
作者：
Pallos, Judit;Bodai, Laszlo;Marsh, J. Lawrence
亨廷顿氏病（HD）与转录失调有关，对组蛋白去乙酰化酶（HDAC）抑制剂的多项研究表明，恢复转录平衡和适当的蛋白质乙酰化的整体方法在治疗上是有希望的。为了确定更有针对性的方法是否有效，我们测试了果蝇中所有hdac对亨廷顿蛋白（Htt）诱导的病理的影响。在锌依赖性或“经典”hdac中，我们发现神经变性对Rpd3水平最敏感。我们还发现，在NAD（+）依赖的III类去乙酰化酶中，遗传或药理学上减少Sir2或Sirt2均可为httd挑战动物提供神经保护，当Rpd3和Sir2同时减少时，神经保护作用更大。我们的实验表明，促进长寿的策略可能不同于那些保护受人类Htt突变挑战的果蝇免受神经变性的策略。这些结果强调了一种以抑制Sir2和可能的联合抑制Sir2和Rpd3的形式治疗HD的新方法。
Huntington's disease (HD) is associated with transcriptional dysregulation, and multiple studies with histone deacetylase (HDAC) inhibitors suggest that global approaches for restoring transcriptional balance and appropriate protein acetylation are therapeutically promising. To determine whether more targeted approaches might be effective, we have tested the impact of all the HDACs in Drosophila on Huntingtin (Htt)-induced pathology. Among the zinc-dependent or 'classic' HDACs, we find that neurodegeneration is most sensitive to levels of Rpd3. We also find that among the NAD(+)-dependent class III deacetylases, genetic or pharmacological reduction of either Sir2 or Sirt2 provides neuroprotection to Htt-challenged animals and that even greater neuroprotection is achieved when Rpd3 and Sir2 are simultaneously reduced. Our experiments suggest that longevity promoting strategies may be distinct from those that protect against neurodegeneration in Drosophila challenged with mutant human Htt. These results highlight a novel therapeutic approach for HD in the form of Sir2 inhibition and possible combinatorial inhibition of Sir2 and Rpd3.