Acetylation of NDUFV1 induced by a newly synthesized HDAC6 inhibitor HGC rescues dopaminergic neuron loss in Parkinson models.
Acetylation of NDUFV1 induced by a newly synthesized HDAC6 inhibitor HGC rescues dopaminergic neuron loss in Parkinson models.
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新合成的 HDAC6 抑制剂 HGC 诱导的 NDUFV1 乙酰化可挽救帕金森模型中的多巴胺能神经元损失
DOI：
10.1016/j.isci.2021.102302
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发表时间：
2021-04-23
期刊：
影响因子：
5.8
通讯作者：
Sun C
中科院分区：
文献类型：
--
作者：
Li B;Yang Y;Wang Y;Zhang J;Ding J;Liu X;Jin Y;Lian B;Ling Y;Sun C
组蛋白去乙酰化酶（HDAC）抑制剂在治疗帕金森病（PD）等神经退行性疾病方面具有巨大的潜力。在这里，我们合成了一种HDAC抑制剂命名为HGC，并检查其在PD模型中的神经保护作用。我们的研究结果表明，HGC保护多巴胺能神经元免受1-甲基-4-苯基吡啶（MPP+）诱导的损伤。此外，在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD模型小鼠中，HGC应用纠正了行为缺陷，改善了中脑中的酪氨酸羟化酶阳性神经元，并维持了线粒体的完整性和功能。从机理上讲，质谱数据显示，HGC刺激NDUFV 1的赖氨酸28处的乙酰化修饰。HGC对HDAC 6的抑制是这种乙酰化修饰的原因。功能测试表明，与HGC一样，NDUFV 1对MPP+损伤具有有益作用。此外，NDUFV 1的敲除消除了HGC的神经保护作用。综上所述，我们的数据表明HGC对治疗PD具有巨大的治疗潜力，NDUFV 1可能是开发抗PD药物的靶点。HGC是HDACs，特别是HDAC 1/6的有效抑制剂HGC在PD模型中保护多巴胺能神经元并减轻PD症状HDAC 6/NDUFV 1轴负责转导其抗PD活性HGC在治疗PD方面具有巨大的治疗潜力生物科学;神经科学;行为神经科学;分子神经科学;系统神经科学;细胞神经科学
It has been shown that histone deacetylase (HDAC) inhibitors hold considerable therapeutic potentials for treating neurodegeneration-related diseases including Parkinson disease (PD). Here, we synthesized an HDAC inhibitor named as HGC and examined its neuroprotective roles in PD models. Our results showed that HGC protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced insults. Furthermore, in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model mice, HGC application rectifies behavioral defects, improves tyrosine hydroxylase-positive neurons in the midbrain, and maintains mitochondrial integrity and functions. Mechanistically, mass spectrometry data revealed that HGC stimulates acetylation modification at lysine 28 of NDUFV1. Inhibition of HDAC6 by HGC is responsible for this acetylation modification. Functional tests showed that, as well as HGC, NDUFV1 exhibits beneficial roles against MPP+ injuries. Moreover, knockdown of NDUFV1 abolishes the neuroprotective roles of HGC. Taken together, our data indicate that HGC has a great therapeutic potential for treating PD and NDUFV1 might be a target for developing drugs against PD. HGC is a potent inhibitor for HDACs, especially HDAC1/6 HGC protects dopaminergic neurons and alleviates PD symptoms in PD models HDAC6/NDUFV1 axis is responsible for transducing its anti-PD activities HGC holds great therapeutic potentials for treating PD Biological Sciences; Neuroscience; Behavioral Neuroscience; Molecular Neuroscience; Systems Neuroscience; Cellular Neuroscience
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DOI：
10.3233/jhd-160226
发表时间：
2016-12-15
期刊：
Journal of Huntington's disease
影响因子：
--
作者：
Chopra V;Quinti L;Khanna P;Paganetti P;Kuhn R;Young AB;Kazantsev AG;Hersch S
通讯作者：
Hersch S
影响因子：
7.3
作者：
Chen, S. H.;Wu, H. M.;Lu, R. B.
通讯作者：
Lu, R. B.
影响因子：
7.3
作者：
Harrison, Ian F.;Crum, William R.;Dexter, David T.
通讯作者：
Dexter, David T.
影响因子：
5.6
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
通讯作者：
Goodson, HV
影响因子：
168.9
作者：
Kalia, Lorraine V.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.