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SIRT2 Inhibition Improves Functional Motor Recovery After Peripheral Nerve Injury.
Neurotherapeutics ( IF 5.7 ) Pub Date : 2020-04-22 , DOI: 10.1007/s13311-020-00860-3
David Romeo-Guitart 1 , Tatiana Leiva-Rodríguez 1 , Caty Casas 1, 2
Affiliation  

Sirtuin-2 (Sirt2) is a member of the NAD (+)-dependent protein deacetylase family involved in neuroprotection, cellular metabolism, homeostasis, and stress responses after injury of the nervous system. So far, no data have been published describing the role of SIRT2 in motor functional recovery after damage. We found that SIRT2 expression and deacetylase activity were increased within motoneurons after axotomy. To shed light onto the biological relevance of this change, we combined in vitro and in vivo models with pharmacological and genetic ablation approaches. We found that SIRT2 KO (knockout) mice exhibited improved functional recovery after sciatic nerve crush. SIRT2 activity blockage, using AK7, increased neurite outgrowth and length in organotypic spinal cord cultures and human cell line models. SIRT2 blockage enhanced the acetyltransferase activity of p300, which in turn increased the levels of an acetylated form of p53 (Ac-p53 k373), histone 3 (Ac-H3K9), and expression of GAP43, a downstream marker of regeneration. Lastly, we verified that p300 acetyltransferase activity is essential for these effects. Our results suggest that bolstering an epigenetic shift that promotes SIRT2 inhibition can be an effective therapy to increase functional recovery after peripheral nerve injury.

中文翻译:

SIRT2 抑制可改善周围神经损伤后的功能性运动恢复。

Sirtuin-2 (Sirt2) 是 NAD (+) 依赖性蛋白脱乙酰酶家族的成员,参与神经保护、细胞代谢、稳态和神经系统损伤后的应激反应。迄今为止,尚未发表任何数据描述 SIRT2 在损伤后运动功能恢复中的作用。我们发现轴突切除术后运动神经元内 SIRT2 表达和脱乙酰酶活性增加。为了阐明这种变化的生物学相关性,我们将体外和体内模型与药理学和遗传消融方法相结合。我们发现 SIRT2 KO(敲除)小鼠在坐骨神经挤压后表现出更好的功能恢复。使用 AK7 阻断 SIRT2 活性可增加器官型脊髓培养物和人类细胞系模型中的神经突生长和长度。SIRT2 阻断增强了 p300 的乙酰转移酶活性,从而增加了乙酰化形式的 p53 (Ac-p53 k373)、组蛋白 3 (Ac-H3K9) 的水平以及再生下游标记 GAP43 的表达。最后,我们证实 p300 乙酰转移酶活性对于这些效果至关重要。我们的结果表明,支持促进 SIRT2 抑制的表观遗传转变可能是促进周围神经损伤后功能恢复的有效疗法。
更新日期:2020-04-23
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