PAK4 suppresses motor neuron degeneration in hSOD1(G93A) -linked amyotrophic lateral sclerosis cell and rat models.
PAK4 suppresses motor neuron degeneration in hSOD1(G93A) -linked amyotrophic lateral sclerosis cell and rat models.
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PAK4 抑制 hSOD1G93A–连锁肌萎缩侧索硬化症细胞和大鼠模型中的运动神经元变性
DOI：
10.1111/cpr.13003
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发表时间：
2021-04
影响因子：
8.5
通讯作者：
Feng H
中科院分区：
文献类型：
--
作者：
Cong C;Liang W;Zhang C;Wang Y;Yang Y;Wang X;Wang S;Huo D;Wang H;Wang D;Feng H
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以运动神经元（motorneurons，MN）进行性丧失为特征的致死性神经退行性疾病。CREB通路介导的细胞凋亡抑制有助于神经元保护，PAK 4在不同细胞类型中激活CREB信号传导。本研究旨在探讨PAK 4在ALS中的作用及其机制。我们通过qRT-PCR分析RNA水平，通过免疫荧光和Western印迹分析蛋白水平，通过流式细胞术和TUNEL染色分析细胞凋亡。进行细胞转染用于体外实验。小鼠脊柱内注射以在体内实验中评估PAK 4功能。进行旋转杆试验以测量运动功能。在ALS的细胞和小鼠模型中，PAK 4的表达和激活随着疾病的进展而显著降低，这是由miR-9 - 5 p的负调控引起的。PAK 4的沉默通过抑制CREB介导的神经保护作用增加MN的凋亡，而PAK 4的过表达通过激活CREB信号传导保护MN免受hSOD 1G 93 A诱导的变性。CREB抑制剂可明显抑制PAK 4的神经保护作用。在ALS模型中，PAK 4/CREB通路被抑制，细胞凋亡增加。体内实验表明，PAK 4在hSOD 1G 93 A小鼠脊髓神经元中的过表达抑制MN变性，延长存活时间并促进CREB通路。PAK 4通过激活CREB信号的抗凋亡作用保护MN免于变性，这表明它可能是ALS的治疗靶点。PAK 4保护MN免于ALS中细胞凋亡的机制的示意图。PAK 4增加CREB水平和激活，导致PGC-1a和Bcl-2上调，从而降低切割的-caspase 3水平，并抑制MN变性。miR-9 - 5 p是导致ALS中PAK 4表达降低的原因。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MN). CREB pathway‐mediated inhibition of apoptosis contributes to neuron protection, and PAK4 activates CREB signalling in diverse cell types. This study aimed to investigate PAK4’s effect and mechanism of action in ALS. We analysed RNA levels by qRT‐PCR, protein levels by immunofluorescence and Western blotting, and apoptosis by flow cytometry and TUNEL staining. Cell transfection was performed for in vitro experiment. Mice were injected intraspinally to evaluate PAK4 function in vivo experiment. Rotarod test was performed to measure motor function. The expression and activation of PAK4 significantly decreased in the cell and mouse models of ALS as the disease progressed, which was caused by the negative regulation of miR‐9‐5p. Silencing of PAK4 increased the apoptosis of MN by inhibiting CREB‐mediated neuroprotection, whereas overexpression of PAK4 protected MN from hSOD1G93A‐induced degeneration by activating CREB signalling. The neuroprotective effect of PAK4 was markedly inhibited by CREB inhibitor. In ALS models, the PAK4/CREB pathway was inhibited, and cell apoptosis increased. In vivo experiments revealed that PAK4 overexpression in the spinal neurons of hSOD1G93A mice suppressed MN degeneration, prolonged survival and promoted the CREB pathway. PAK4 protects MN from degeneration by activating the anti‐apoptotic effects of CREB signalling, suggesting it may be a therapeutic target in ALS. Schematic representation of the mechanism of PAK4 protecting MN from apoptosis in ALS. PAK4 increases CREB levels and activation, leading to the upregulation of PGC‐1a and Bcl‐2, thereby decreasing cleaved‐caspase3 levels, and inhibiting MN degeneration. miR‐9‐5p is responsible for the decreased expression of PAK4 in ALS.
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影响因子：
11.4
作者：
Abo, A;Qu, J;Minden, A
通讯作者：
Minden, A
影响因子：
5.3
作者：
Espana, Judit;Valero, Jorge;Saura, Carlos A.
通讯作者：
Saura, Carlos A.
影响因子：
3.5
作者：
Chaturvedi, Rajnish Kumar;Hennessey, Thomas;Beal, M. Flint
通讯作者：
Beal, M. Flint
PAK4 抑制 hSOD1G93A–连锁肌萎缩侧索硬化症细胞和大鼠模型中的运动神经元变性
影响因子：
8.5
作者：
Cong C;Liang W;Zhang C;Wang Y;Yang Y;Wang X;Wang S;Huo D;Wang H;Wang D;Feng H
通讯作者：
Feng H
影响因子：
4.8
作者：
Gnesutta, N;Qu, J;Minden, A
通讯作者：
Minden, A