Differential Sirtuin Expression Patterns in Amyotrophic Lateral Sclerosis (ALS) Postmortem Tissue: Neuroprotective or Neurotoxic Properties of Sirtuins in ALS?
Differential Sirtuin Expression Patterns in Amyotrophic Lateral Sclerosis (ALS) Postmortem Tissue: Neuroprotective or Neurotoxic Properties of Sirtuins in ALS?
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DOI：
10.1159/000338048
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发表时间：
2013-01-01
影响因子：
3
通讯作者：
Petri, Susanne
中科院分区：
文献类型：
--
作者：
Koerner, Sonja;Boeselt, Sebastian;Petri, Susanne
背景/目标：SIRT1-7; III类组蛋白脱乙酰酶）调节年龄相关的神经变性疾病如肌萎缩侧索硬化（ALS）的基本机制。我们评估了sirtuins在人死后ALS和对照脑和脊髓中的表达水平。方法和结果：通过实时定量PCR，在初级运动皮质（白色和灰质）的匀浆中检测到SIRT 1和SIRT 2的显著减少，而在脊髓匀浆中没有差异。当通过原位杂交组织化学和免疫组织化学专门分析灰质（中央前回的皮质层I-VI，脊髓的腹侧/背角）中的mRNA和蛋白质表达时，我们发现ALS中SIRT 1、SIRT 2和SIRT 5的水平增加，这对于脊髓中的SIRT 1和SIRT 5 mRNA是显著的。结论：我们的研究结果表明，一般减少SIRT 1和SIRT 2在ALS的初级运动皮层，而原位杂交组织化学和免疫组化显示神经元特异性上调SIRT 1，SIRT 2和SIRT 5，特别是在脊髓。已经描述了SIRT 1和SIRT 2的相反作用：虽然SIRT 1活化主要与神经保护相关，但SIRT 2上调对神经元细胞有毒。因此，ALS的新治疗方法可以靶向SIRT 1激活或SIRT 2抑制。版权所有（c）2012 S. Karger AG，巴塞尔
Background/Aims: Sirtuins (SIRT1-7; class III histone deactylases) modulate fundamental mechanisms in age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We assessed the expression levels of sirtuins in human postmortem ALS and control brain and spinal cord. Methods and Results: By quantitative real-time PCR, a significant reduction of SIRT1 and SIRT2 was detected in homogenates of the primary motor cortex (white and gray matter), while there were no differences in spinal cord homogenates. When specifically analyzing mRNA and protein expression in the gray matter (cortical layers I-VI of the pre-central gyrus, ventral/dorsal horn of the spinal cord) by in situ hybridization histochemistry and immunohistochemistry, we found increased levels of SIRT1, SIRT2 and SIRT5 in ALS which were significant for SIRT1 and SIRT5 mRNA in the spinal cord. Conclusion: Our results indicate a general reduction of SIRT1 and SIRT2 in ALS primary motor cortex, while in situ hybridization histochemistry and immunohistochemistry showed neuron-specific upregulation of SIRT1, SIRT2 and SIRT5, particularly in the spinal cord. Opposed effects have been described for SIRT1 and SIRT2: while SIRT1 activation is mainly associated with neuroprotection, SIRT2 upregulation is toxic to neuronal cells. Novel therapeutic approaches in ALS could therefore target SIRT1 activation or SIRT2 inhibition. Copyright (c) 2012 S. Karger AG, Basel