Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS.
Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS.
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DOI：
10.1038/s41419-018-0624-8
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发表时间：
2018-05-22
影响因子：
9
通讯作者：
Schiavo G
中科院分区：
文献类型：
--
作者：
Gibbs KL;Kalmar B;Rhymes ER;Fellows AD;Ahmed M;Whiting P;Davies CH;Greensmith L;Schiavo G
肌萎缩侧索硬化症(ALS)是一种由上下运动神经元变性引起的致死性神经退行性疾病。在ALS的SOD1G93A小鼠模型中，在症状前就观察到轴突运输缺陷，并被认为在运动神经元退化以及其他神经系统病理中发挥作用，如阿尔茨海默病和遗传性神经病变。在这项研究中，我们筛选了一个小分子激酶抑制剂的文库，以识别信号内体轴突逆行运输的药理增强剂，这可能被用来在患病神经元中使这一过程的速率正常化。P38丝裂原活化蛋白激酶(P38 MAPK)的抑制剂(P38 MAPK)在此筛选中被发现，并被发现纠正了培养的原代SOD1G93A运动神经元中信号内体轴突逆行运输的缺陷。体外基因敲除实验表明，p38MAPK的α亚型(p38MAPKα)是SOD1G93A诱导的转运缺陷的唯一亚型。此外，我们发现，p38MAPKα抑制剂的急性治疗恢复了早期有症状的SOD1G93A小鼠体内轴突逆行运输的生理速率。我们的发现证明了p38MAPKα在轴突逆行运输中的致病作用，并确定了一种潜在的ALS治疗策略。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1G93A mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer’s disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1G93A motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1G93A-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1G93A mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.
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影响因子：
6.1
作者：
Brady ST;Morfini GA
通讯作者：
Morfini GA
DOI：
10.1038/nrd2999
发表时间：
2009-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Kandan, Nicholas M.;Pigino, Gustavo F.;Brady, Scott T.;Lazarov, Orly;Binder, Lester I.;Morfini, Gerardo A.
通讯作者：
Morfini, Gerardo A.
影响因子：
5.9
作者：
Bhinge A;Namboori SC;Zhang X;VanDongen AMJ;Stanton LW
通讯作者：
Stanton LW
影响因子：
3
作者：
Gibbs KL;Kalmar B;Sleigh JN;Greensmith L;Schiavo G
通讯作者：
Schiavo G