Leng Yan, Chuang De-Maw
Molecular Neurobiology Section, Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA.
J Neurosci. 2006 Jul 12;26(28):7502-12. doi: 10.1523/JNEUROSCI.0096-06.2006.
Emerging evidence suggests that alpha-synuclein (alpha-syn), which is traditionally thought to have a pathophysiological role in neurodegenerative diseases, can have neuroprotective effects. This study aimed to investigate whether endogenous alpha-syn in neurons can be induced by valproic acid (VPA), a mood-stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, and if so, whether the alpha-syn induction is neuroprotective. VPA treatment of rat cerebellar granule cells caused a robust dose- and time-dependent increase in levels of alpha-syn protein and mRNA and in the intensity of alpha-syn immunostaining. Knockdown of VPA-induced alpha-syn overexpression with alpha-syn antisense oligonucleotides or siRNA completely blocked VPA-induced neuroprotection. alpha-Syn knockdown also exacerbated glutamate neurotoxicity, stimulated the expression of the proapoptotic gene ubiquitin-conjugating enzyme E2N, and downregulated the expression of the anti-apoptotic gene Bcl-2. Induction of alpha-syn by VPA was associated with inhibition of HDAC activity, resulting in hyperacetylation of histone H3 in the alpha-syn promoter and a marked increase in alpha-syn promoter activity. Moreover, VPA-induced alpha-syn induction and neuroprotection were mimicked by HDAC inhibitors sodium 4-phenylbutyrate and trichostatin A (TSA). alpha-syn was also induced by VPA in rat cerebral cortical neurons. Additionally, treatment of rats with VPA, sodium butyrate, or TSA markedly increased alpha-syn protein levels in the cortex and cerebellum. Together, our results demonstrate for the first time that VPA induces alpha-syn in neurons through inhibition of HDAC and that this alpha-syn induction is critically involved in neuroprotection against glutamate excitotoxicity. Clinically, VPA may represent a suitable treatment for excitotoxicity-related neurodegenerative diseases.
新出现的证据表明，传统上认为在神经退行性疾病中具有病理生理作用的α-突触核蛋白（α-syn）可能具有神经保护作用。本研究旨在调查丙戊酸（VPA），一种情绪稳定剂、抗惊厥药和组蛋白脱乙酰酶（HDAC）抑制剂，是否能诱导神经元中的内源性α-syn，如果可以，α-syn的诱导是否具有神经保护作用。用VPA处理大鼠小脑颗粒细胞导致α-syn蛋白和mRNA水平以及α-syn免疫染色强度呈剂量和时间依赖性显著增加。用α-syn反义寡核苷酸或小干扰RNA敲低VPA诱导的α-syn过表达完全阻断了VPA诱导的神经保护作用。α-syn敲低还加剧了谷氨酸神经毒性，刺激了促凋亡基因泛素结合酶E2N的表达，并下调了抗凋亡基因Bcl-2的表达。VPA诱导α-syn与HDAC活性抑制有关，导致α-syn启动子中组蛋白H3的高乙酰化和α-syn启动子活性显著增加。此外，HDAC抑制剂4-苯丁酸钠和曲古抑菌素A（TSA）模拟了VPA诱导的α-syn诱导和神经保护作用。VPA在大鼠大脑皮质神经元中也诱导了α-syn。此外，用VPA、丁酸钠或TSA处理大鼠显著增加了皮质和小脑中α-syn蛋白水平。总之，我们的结果首次证明VPA通过抑制HDAC诱导神经元中的α-syn，并且这种α-syn诱导在对抗谷氨酸兴奋性毒性的神经保护中起关键作用。临床上，VPA可能是与兴奋性毒性相关的神经退行性疾病的一种合适治疗方法。
