HDAC6 regulates mitochondrial transport in hippocampal neurons.
HDAC6 regulates mitochondrial transport in hippocampal neurons.
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DOI：
10.1371/journal.pone.0010848
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发表时间：
2010-05-26
期刊：
影响因子：
3.7
通讯作者：
Edelman DB
中科院分区：
文献类型：
--
作者：
Chen S;Owens GC;Makarenkova H;Edelman DB
微管蛋白是细胞质II类组蛋白脱乙酰酶HDAC 6的主要底物。HDAC 6的抑制导致更高水平的乙酰化微管蛋白和增强的马达蛋白驱动蛋白-1与微管蛋白的结合，这促进了货物沿沿着的运输。因此，微管依赖性细胞内运输可以通过调节HDAC 6的活性来调节。我们之前已经表明，神经调节剂5-羟色胺通过Akt-GSK 3 β信号通路增加海马神经元中的线粒体运动。在这里，我们证明了HDAC 6在这个信号通路中的作用。我们发现，存在的tubacin，一个特定的HDAC 6抑制剂，显着增强海马神经元中的线粒体运动，而niltubacin，一个无活性的tubacin类似物，没有影响。与对照培养物相比，在用微管蛋白处理的神经元中发现更高水平的乙酰化微管蛋白，并且更多的驱动蛋白-1与从这些神经元分离的线粒体相关。抑制GSK 3 β可降低细胞质脱乙酰酶活性，增加微管蛋白乙酰化，而阻断Akt（磷酸化和下调GSK 3 β）可增加细胞质脱乙酰酶活性，减少微管蛋白乙酰化。一致地，5-HT、8-OH-DPAT（一种特异性5-HT 1A受体激动剂）或氟西汀（一种5-HT再摄取抑制剂）的给药增加了微管蛋白乙酰化。发现GSK 3 β与HDAC 6共定位于海马神经元中，并且GSK 3 β的抑制导致抗体与磷酸丝氨酸-22（HDAC 6中潜在的GSK 3 β磷酸化位点）的结合减少。因此，GSK 3 β可能通过磷酸化调节HDAC 6活性。这项研究表明HDAC 6在线粒体转运的调节中起着重要作用。HDAC 6和GSK 3 β之间的联系，在这里建立，对我们理解神经退行性疾病具有重要意义。特别是，在阿尔茨海默病和帕金森病等疾病中观察到的异常线粒体转运可能是由GSK 3 β对HDAC 6的错误调节引起的。因此，HDAC 6可能构成治疗这些疾病的有吸引力的靶标。
Tubulin is a major substrate of the cytoplasmic class II histone deacetylase HDAC6. Inhibition of HDAC6 results in higher levels of acetylated tubulin and enhanced binding of the motor protein kinesin-1 to tubulin, which promotes transport of cargoes along microtubules. Microtubule-dependent intracellular trafficking may therefore be regulated by modulating the activity of HDAC6. We have shown previously that the neuromodulator serotonin increases mitochondrial movement in hippocampal neurons via the Akt-GSK3β signaling pathway. Here, we demonstrate a role for HDAC6 in this signaling pathway. We found that the presence of tubacin, a specific HDAC6 inhibitor, dramatically enhanced mitochondrial movement in hippocampal neurons, whereas niltubacin, an inactive tubacin analog, had no effect. Compared to control cultures, higher levels of acetylated tubulin were found in neurons treated with tubacin, and more kinesin-1 was associated with mitochondria isolated from these neurons. Inhibition of GSK3β decreased cytoplasmic deacetylase activity and increased tubulin acetylation, whereas blockade of Akt, which phosphorylates and down-regulates GSK3β, increased cytoplasmic deacetylase activity and decreased tubulin acetylation. Concordantly, the administration of 5-HT, 8-OH-DPAT (a specific 5-HT1A receptor agonist), or fluoxetine (a 5-HT reuptake inhibitor) increased tubulin acetylation. GSK3β was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3β resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3β phosphorylation site in HDAC6. GSK3β may therefore regulate HDAC6 activity by phosphorylation. This study demonstrates that HDAC6 plays an important role in the modulation of mitochondrial transport. The link between HDAC6 and GSK3β, established here, has important implications for our understanding of neurodegenerative disorders. In particular, abnormal mitochondrial transport, which has been observed in such disorders as Alzheimer's disease and Parkinson's disease, could result from the misregulation of HDAC6 by GSK3β. HDAC6 may therefore constitute an attractive target in the treatment of these disorders.
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影响因子：
4.3
作者：
Matthias, Patrick;Yoshida, Minoru;Khochbin, Saadi
通讯作者：
Khochbin, Saadi
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
阿尔茨海默氏病的GSK3假设。
影响因子：
4.7
作者：
Hooper C;Killick R;Lovestone S
通讯作者：
Lovestone S
DOI：
10.1083/jcb.200611128
发表时间：
2007-09-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Olzmann JA;Li L;Chudaev MV;Chen J;Perez FA;Palmiter RD;Chin LS
通讯作者：
Chin LS