Department of Neurology, Hannover Medical School, Hannover, Germany.
Neurodegener Dis. 2013;11(3):141-52. doi: 10.1159/000338048. Epub 2012 Jul 10.
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.
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 precentral 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.
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.
背景/目的：沉默调节蛋白（SIRT1-7；III 类组蛋白去乙酰化酶）调节与年龄相关的神经退行性疾病（如肌萎缩侧索硬化症，ALS）相关的基本机制。我们评估了 SIRT 在人死后 ALS 和对照大脑和脊髓中的表达水平。
通过定量实时 PCR，在原发性运动皮层（白质和灰质）的匀浆中检测到 SIRT1 和 SIRT2 的表达显著降低，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特异性分析灰质（中央前回的皮质层 I-VI、脊髓腹侧/背角）中的 mRNA 和蛋白表达时，我们发现 ALS 中 SIRT1、SIRT2 和 SIRT5 的水平增加，这在脊髓中 SIRT1 和 SIRT5 mRNA 中是显著的。
我们的结果表明 ALS 原发性运动皮层中 SIRT1 和 SIRT2 的普遍减少，而原位杂交组织化学和免疫组织化学显示 SIRT1、SIRT2 和 SIRT5 在神经元中特异性上调，特别是在脊髓中。SIRT1 和 SIRT2 具有相反的作用：虽然 SIRT1 激活主要与神经保护相关，SIRT2 上调对神经元细胞有毒性。因此，ALS 的新治疗方法可以靶向 SIRT1 激活或 SIRT2 抑制。
