Golpich Mojtaba, Amini Elham, Hemmati Fatemeh, Ibrahim Norlinah Mohamed, Rahmani Behrouz, Mohamed Zahurin, Raymond Azman Ali, Dargahi Leila, Ghasemi Rasoul, Ahmadiani Abolhassan
Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Pharmacol Res. 2015 Jul;97:16-26. doi: 10.1016/j.phrs.2015.03.010. Epub 2015 Mar 28.
Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3β), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (α-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3β in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3β has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3β inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3β and several cellular processes involved in the pathogenesis of PD, including the accumulation of α-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3β inhibitors as a potential therapeutic strategy in PD.
糖原合酶激酶3（GSK-3）失调在众多疾病的发病机制中起重要作用，影响包括神经炎症和神经退行性疾病在内的中枢神经系统（CNS）。多条证据表明GSK-3及其细胞和分子信号级联在神经炎症控制中起关键作用。糖原合酶激酶3β（GSK-3β）是GSK-3异构体之一，在神经元凋亡中起主要作用，其抑制作用可降低α-突触核蛋白（α-Synuclein）的表达，这使得该激酶成为神经退行性疾病有吸引力的治疗靶点。帕金森病（PD）是一种慢性神经退行性运动障碍，其特征是黑质致密部神经元凋亡导致多巴胺能神经元进行性大量丧失以及纹状体中多巴胺耗竭，进而导致病理和临床异常。因此，了解GSK-3β在PD中的作用将增强我们对该疾病发病机制基础基本机制的认识，并有助于确定新的治疗途径。近年来，已证明GSK-3β在调节多种细胞功能中起重要作用，这促使人们努力开发GSK-3β抑制剂作为治疗药物。在本综述中，我们总结了GSK-3信号通路及其与神经炎症的关联。此外，我们强调了GSK-3β与PD发病机制中涉及的几个细胞过程之间的相互作用，包括α-突触核蛋白聚集体的积累、氧化应激和线粒体功能障碍。最后，我们讨论了GSK-3β抑制剂作为PD潜在治疗策略的相关内容。
