When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease.
When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease.
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DOI：
10.3390/ijms22115911
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发表时间：
2021-05-31
影响因子：
5.6
通讯作者：
D'Mello SR
中科院分区：
文献类型：
--
作者：
D'Mello SR
阿尔茨海默病（AD）是一种以海马和大脑皮层中的选择性神经变性导致的认知下降为特征的大多数散发性脑疾病，而亨廷顿病（HD）是一种单基因遗传性疾病，其特征在于纹状体中的选择性神经变性导致的运动异常和精神障碍。尽管针对这些疾病进行了大量临床试验，但都没有成功。在过去的三十年里，大量实验室进行的研究表明，常见激酶的异常作用在AD和HD以及其他几种神经退行性疾病的发病机制中起着关键作用。在这些激酶中突出的是糖原合成酶激酶（GSK 3）、p38促分裂原活化蛋白激酶（MAPK）和一些细胞周期蛋白依赖性激酶（CDK）。在简要总结了AD和HD的分子和细胞生物学后，本文综述了这三组激酶在大脑中的作用以及这两种神经退行性疾病的发病机制。还讨论了靶向GSK3，p38 MAPK和CDKS作为有效治疗剂的潜力，并简要讨论了最近开发的同时靶向两种或所有三种激酶的药物的利用。多激酶抑制剂本身或与目前正在使用的策略（如免疫疗法或分泌酶抑制剂用于AD和敲低用于HD）联合使用，可能是治疗这些致命性神经退行性疾病的更有效方法。
Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.
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影响因子：
9
作者：
Aubrecht TG;Faden AI;Sabirzhanov B;Glaser EP;Roelofs BA;Polster BM;Makarevich O;Stoica BA
通讯作者：
Stoica BA
影响因子：
3.1
作者：
Ashabi, Ghorbangol;Alamdary, Shabnam Zeighamy;Khodagholi, Fariba
通讯作者：
Khodagholi, Fariba
影响因子：
5
作者：
Baskota, Swikrity Upadhyay;Lopez, Oscar L.;Greenamyre, J. Timothy;Kofler, Julia
通讯作者：
Kofler, Julia
影响因子：
4.2
作者：
Bartzokis G
通讯作者：
Bartzokis G
影响因子：
4.8
作者：
Akashiba, Hiroki;Ikegaya, Yuji;Matsuki, Norio
通讯作者：
Matsuki, Norio