Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model
Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model
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DOI：
10.1523/jneurosci.1139-07.2007
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发表时间：
2007-05-23
影响因子：
5.3
通讯作者：
Loeffler, Jean-Philippe
中科院分区：
文献类型：
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作者：
Rouaux, Caroline;Panteleeva, Irina;Loeffler, Jean-Philippe
肌萎缩侧索硬化症 (ALS) 的特点是运动神经元 (MN) 变性、全身无力和肌肉萎缩。 MN 的过早死亡被认为是这种疾病发病的决定因素。在表达 G86R 突变体超氧化物歧化酶 1 ( mSOD1) 的 ALS 转基因小鼠模型中，我们之前证明了退化 MN 细胞核中 CREB（cAMP 反应元件结合蛋白）结合蛋白 (CBP) 和组蛋白乙酰化水平特异性降低。我们在此表明，在 MN 衍生细胞系中，氧化应激和 mSOD1 过表达均可通过转录抑制影响 CBP 水平。组蛋白脱乙酰酶抑制剂 (HDACi) 治疗能够重置适当的乙酰化水平，并在体外表现出针对氧化应激的有效神经保护能力。有趣的是，HDACi 还上调了 MN 中的 CBP 转录表达。此外，当体内注射 HDACi 丙戊酸钠 (VPA) 至 G86R 小鼠体内时，HDACi 丙戊酸钠 (VPA) 维持了脊髓中的正常乙酰化水平，有效恢复了 MN 中的 CBP 水平，并显着防止了这些动物的 MN 死亡。然而，尽管有神经保护作用，治疗动物的平均存活率并未显着提高（<5%），并且它们死亡时表现出典型的 ALS 症状。 VPA 无法阻止神经肌肉接头的破坏，尽管它稍微延迟了运动能力下降的发生并在一定程度上延缓了肌肉萎缩。总之，这些数据表明，神经保护可以改善疾病的发生，但也清楚地提供了证据，表明可以将 MN 存活率与整个动物存活率分开，并指出神经肌肉接头扰动是 ALS 发作的主要事件。
Amyotrophic lateral sclerosis ( ALS) is characterized by motoneuron ( MN) degeneration, generalized weakness, and muscle atrophy. The premature death of MNs is thought to be a determinant in the onset of this disease. In a transgenic mouse model of ALS expressing the G86R mutant superoxide dismutase 1 ( mSOD1), we demonstrated previously that CREB ( cAMP response element-binding protein)binding protein ( CBP) and histone acetylation levels were specifically decreased in nuclei of degenerating MNs. We show here that oxidative stress and mSOD1 overexpression can both impinge on CBP levels by transcriptional repression, in an MN-derived cell line. Histone deacetylase inhibitor ( HDACi) treatment was able to reset proper acetylation levels and displayed an efficient neuroprotective capacity against oxidative stress in vitro. Interestingly, HDACi also upregulated CBP transcriptional expression in MNs. Moreover, when injected to G86R mice in vivo, the HDACi sodium valproate ( VPA) maintained normal acetylation levels in the spinal cord, efficiently restored CBP levels in MNs, and significantly prevented MN death in these animals. However, despite neuroprotection, mean survival of treated animals was not significantly improved ( < 5%), and they died presenting the classical ALS symptoms. VPA was not able to prevent disruption of neuromuscular junctions, although it slightly delayed the onset of motor decline and retarded muscular atrophy to some extent. Together, these data show that neuroprotection can improve disease onset, but clearly provide evidence that one can uncouple MN survival from whole-animal survival and point to the neuromuscular junction perturbation as a primary event of ALS onset.