HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons.
HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons.
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DOI：
10.1371/journal.pone.0042983
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mook-Jung I
中科院分区：
文献类型：
--
作者：
Kim C;Choi H;Jung ES;Lee W;Oh S;Jeon NL;Mook-Jung I
尽管轴突运输的破坏是神经退行性疾病包括阿尔茨海默病（AD）的重要病理生理因素，但轴突运输的破坏与AD的发病机制之间的关系知之甚少。考虑到α-微管蛋白乙酰化是轴突运输的一个重要因素，而Aβ损害线粒体轴突运输，我们在微流控系统中用Aβ培养的海马神经元中操纵α-微管蛋白乙酰化水平，并检查其对线粒体轴突运输的影响。我们发现，抑制组蛋白去乙酰化酶6（HDAC 6），使α-微管蛋白去乙酰化，显著恢复了顺行和逆行轴突运输中线粒体的速度和运动性，这将被Aβ破坏。HDAC 6的抑制也使被Aβ缩短的线粒体长度恢复到正常水平。这些结果表明，HDAC 6的抑制显著地拯救海马神经元免于Aβ诱导的线粒体轴突运输以及线粒体长度的损伤。本文中给出的结果将HDAC 6确定为线粒体转运以及延伸的重要调节剂，因此，其药理学抑制有助于改善Aβ处理的神经元中的线粒体动力学的潜在靶点。
Even though the disruption of axonal transport is an important pathophysiological factor in neurodegenerative diseases including Alzheimer's disease (AD), the relationship between disruption of axonal transport and pathogenesis of AD is poorly understood. Considering that α-tubulin acetylation is an important factor in axonal transport and that Aβ impairs mitochondrial axonal transport, we manipulated the level of α-tubulin acetylation in hippocampal neurons with Aβ cultured in a microfluidic system and examined its effect on mitochondrial axonal transport. We found that inhibiting histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, significantly restored the velocity and motility of the mitochondria in both anterograde and retrograde axonal transports, which would be otherwise compromised by Aβ. The inhibition of HDAC6 also recovered the length of the mitochondria that had been shortened by Aβ to a normal level. These results suggest that the inhibition of HDAC6 significantly rescues hippocampal neurons from Aβ-induced impairment of mitochondrial axonal transport as well as mitochondrial length. The results presented in this paper identify HDAC6 as an important regulator of mitochondrial transport as well as elongation and, thus, a potential target whose pharmacological inhibition contributes to improving mitochondrial dynamics in Aβ treated neurons.
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影响因子：
3.7
作者：
Cha MY;Han SH;Son SM;Hong HS;Choi YJ;Byun J;Mook-Jung I
通讯作者：
Mook-Jung I
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
4.7
作者：
Ding H;Dolan PJ;Johnson GV
通讯作者：
Johnson GV
影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
DOI：
10.1073/pnas.1006586107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu