Histone acetylation inhibitors promote axon growth in adult dorsal root ganglia neurons.
Histone acetylation inhibitors promote axon growth in adult dorsal root ganglia neurons.
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DOI：
10.1002/jnr.23573
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发表时间：
2015-08
影响因子：
4.2
通讯作者：
Smith GM
中科院分区：
文献类型：
--
作者：
Lin S;Nazif K;Smith A;Baas PW;Smith GM
脊髓损伤后引导受损轴突再生的内在机制仍然知之甚少。操纵成熟神经元中关键蛋白的翻译后修饰可以重新激活损伤后的生长机制。一种这样的修饰是乙酰化，这是一个可逆的过程，由两个相互对立的酶家族控制，组蛋白脱乙酰基酶(HDAC)和组蛋白乙酰转移酶(HATS)。细胞核中的乙酰化组蛋白与促生长基因的上调有关，而轴浆中去乙酰化的微管蛋白与更不稳定的微管有关，有利于轴突的生长。在本研究中，我们研究了HAT抑制剂和HDAC抑制剂对培养的成年背根神经节(DRG)神经元的影响。我们发现，使用羽扇豆酸或CPTH2抑制HATS可以促进轴突生长，而使用TSA或Tubacin抑制HDAC则抑制轴突生长。此外，羽扇豆酸增加了能够穿过抑制的硫酸软骨素蛋白多糖(CSPG)边界的轴突的数量。组蛋白乙酰化而不是微管蛋白乙酰化水平受到HAT抑制剂的影响，而在HDAC抑制剂Tubacin存在下，微管蛋白乙酰化水平增加。虽然微管稳定剂紫杉醇对DRG轴突的长度没有影响，但诺康唑减少了轴突的长度。虽然机制基础还需要进一步的研究，但我们的数据表明，HAT的抑制剂可以促进成年DRG神经元的轴突生长，有可能帮助神经胶质瘢痕产生的抑制底物上的轴突生长。
Intrinsic mechanisms that guide damaged axons to regenerate following spinal cord injury remain poorly understood. Manipulation of posttranslational modifications of key proteins in mature neurons could re-invigorate growth machinery after injury. One such modification is acetylation, a reversible process controlled by two enzyme families acting in opposition, the Histone Deacetylases (HDACs) and the Histone Acetyl Transferases (HATs). While acetylated histones in the nucleus is associated with upregulation of growth promoting genes, de-acetylated tubulin in the axoplasm is associated with more labile microtubules, conducive to axon growth. In this study we investigated the effects of HAT inhibitors and HDAC inhibitors on cultured adult dorsal root ganglia (DRG) neurons. We found that inhibition of HATs, using Anacardic Acid or CPTH2, improved axon outgrowth, while inhibition of HDACs using TSA or Tubacin, inhibited axon growth. Furthermore, Anacardic Acid increased the number of axons able to cross an inhibitory chondroitin sulfate proteoglycan (CSPG) border. Histone acetylation, but not tubulin acetylation levels, was affected by HAT inhibitors, whereas tubulin acetylation levels were increased in the presence of HDAC inhibitor Tubacin. Although microtubule stabilizing drug taxol did not have an effect on the lengths of DRG axons, nocodazole decreased axon lengths. While the mechanistic basis will require future studies, our data show that inhibitors of HAT can augment axon growth in adult DRG neurons, with the potential of aiding axon growth over inhibitory substrates produced by the glial scar.