Department of Neurobiology, Civitan International Research Center, The University of Alabama at Birmingham Birmingham, AL, USA.
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago Chicago, IL, USA.
Front Cell Neurosci. 2014 Mar 7;8:68. doi: 10.3389/fncel.2014.00068. eCollection 2014.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α-tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.
雷特综合征（RTT）是一种神经发育障碍，由转录调节剂甲基化CpG 结合蛋白 2（MECP2）的功能丧失突变引起。MeCP2 的最主要基因靶标之一是脑源性神经营养因子（BDNF），它是一种调节活性依赖性突触发育、功能和可塑性的有效因子。BDNF 信号转导功能障碍已在 RTT 疾病进展的几种病理生理机制中得到证实。为了评估 BDNF 运输的动力学是否受 Mecp2 缺失的影响，我们通过延时荧光成像分析了培养海马神经元中标记有黄色荧光蛋白（YFP）的 BDNF 的运动。我们发现，BDNF-YFP 的顺行和逆行囊泡运输在 Mecp2 敲除海马神经元中均受到显著损害。组蛋白去乙酰化酶 6（HDAC6）的选择性抑制剂在神经退行性疾病中具有神经保护作用，并刺激含 BDNF 的致密核心囊泡的微管依赖性囊泡运输。在这里，我们显示选择性的 HDAC6 抑制剂 Tubastatin-A 通过增加α-微管蛋白乙酰化，增加了 Mecp2 敲除神经元中 BDNF-YFP 囊泡在两个方向上的速度。Tubastatin-A 还将 Mecp2 敲除神经元中的 BDNF 释放恢复到与野生型神经元相当的活性依赖性水平。这些发现表明，选择性的 HDAC6 抑制剂是一种潜在的药理学策略，可以逆转由 BDNF 信号转导受损引起的 RTT 中的细胞和突触损伤。
