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酪氨酸激酶:多种神经退行性疾病相关进程交汇点上的多面受体

Tyrosine kinases: multifaceted receptors at the intersection of several neurodegenerative disease-associated processes.

作者信息

Stevenson Max, Algarzae Norah K, Moussa Charbel

机构信息

The Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, Department of Neurology, Georgetown University Medical Center, Washington, DC, United States.

Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

出版信息

Front Dement. 2024 Aug 16;3:1458038. doi: 10.3389/frdem.2024.1458038. eCollection 2024.

Abstract

Tyrosine kinases (TKs) are catalytic enzymes activated by auto-phosphorylation that function by phosphorylating tyrosine residues on downstream substrates. Tyrosine kinase inhibitors (TKIs) have been heavily exploited as cancer therapeutics, primarily due to their role in autophagy, blood vessel remodeling and inflammation. This suggests tyrosine kinase inhibition as an appealing therapeutic target for exploiting convergent mechanisms across several neurodegenerative disease (NDD) pathologies. The overlapping mechanisms of action between neurodegeneration and cancer suggest that TKIs may play a pivotal role in attenuating neurodegenerative processes, including degradation of misfolded or toxic proteins, reduction of inflammation and prevention of fibrotic events of blood vessels in the brain. In this review, we will discuss the distinct roles that select TKs have been shown to play in various disease-associated processes, as well as identify TKs that have been explored as targets for therapeutic intervention and associated pharmacological agents being investigated as treatments for NDDs.

摘要

酪氨酸激酶(TKs)是通过自身磷酸化激活的催化酶,其作用是使下游底物上的酪氨酸残基磷酸化。酪氨酸激酶抑制剂(TKIs)已被广泛用作癌症治疗药物,主要是因为它们在自噬、血管重塑和炎症中发挥作用。这表明酪氨酸激酶抑制作为一个有吸引力的治疗靶点,可用于利用多种神经退行性疾病(NDD)病理中的趋同机制。神经退行性变和癌症之间重叠的作用机制表明,TKIs可能在减轻神经退行性过程中起关键作用,包括错误折叠或有毒蛋白质的降解、炎症的减轻以及预防大脑血管的纤维化事件。在这篇综述中,我们将讨论特定TKs在各种疾病相关过程中所发挥的不同作用,以及确定已被探索作为治疗干预靶点的TKs和正在作为NDDs治疗药物进行研究的相关药理剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4776/11361951/820d439d7334/frdem-03-1458038-g0001.jpg

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