Naim Alkusha, Farooqui Azhar Mahmood, Khan Mohammad Irfan, Akhtar Juber, Ahmad Asad, Islam Anas
Department of Pharmacy, Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India.
Integral Institute of Medical Sciences and Research, Integral University, Lucknow, Uttar Pradesh, India.
Eur J Neurosci. 2025 Jun;61(11):e70156. doi: 10.1111/ejn.70156.
Neurodegenerative diseases are characterized by progressive neuronal loss and dysfunction, with protein kinases playing crucial roles in their pathogenesis. This article explores the involvement of protein kinases in these disorders, focusing on their contributions to disease mechanisms, potential as therapeutic targets and challenges in developing effective treatments. In Alzheimer's disease, kinases such as CDK5, GSK3β and MARK4 are implicated in tau hyperphosphorylation and the formation of neurofibrillary tangles. Kinases also regulate amyloid-β processing and plaque formation. In Parkinson's disease, LRRK2, PINK1 and other kinases contribute to α-synuclein pathology, mitochondrial dysfunction and neuroinflammation. LRRK2 inhibitors and PROTACs have shown promise in preclinical models. Huntington's disease involves altered kinase activity, with CK2, GSK3 and MAPK pathways influencing mutant huntingtin toxicity and aggregation. Kinases are also implicated in less common neurodegenerative diseases, such as ALS and spinocerebellar ataxias. Despite the therapeutic potential of targeting kinases, challenges remain, including the complexity of kinase networks, blood-brain barrier permeability and the lack of robust biomarkers. Emerging technologies, such as covalent inhibitors, targeted protein degradation and combination therapies, offer new avenues for addressing these challenges and developing more effective treatments for neurodegenerative diseases.
神经退行性疾病的特征是神经元进行性丧失和功能障碍，蛋白激酶在其发病机制中起关键作用。本文探讨了蛋白激酶在这些疾病中的作用，重点关注它们对疾病机制的贡献、作为治疗靶点的潜力以及开发有效治疗方法所面临的挑战。在阿尔茨海默病中，诸如细胞周期蛋白依赖性激酶5（CDK5）、糖原合成酶激酶3β（GSK3β）和微管亲和调节激酶4（MARK4）等激酶与tau蛋白过度磷酸化及神经原纤维缠结的形成有关。激酶还调节淀粉样β蛋白的加工和斑块形成。在帕金森病中，富含亮氨酸重复激酶2（LRRK2）、帕金森病相关蛋白1（PINK1）和其他激酶促成了α-突触核蛋白病变、线粒体功能障碍和神经炎症。LRRK2抑制剂和蛋白酶体靶向嵌合体（PROTACs）在临床前模型中已显示出前景。亨廷顿病涉及激酶活性改变，酪蛋白激酶2（CK2）、糖原合成酶激酶3（GSK3）和丝裂原活化蛋白激酶（MAPK）信号通路影响突变型亨廷顿蛋白的毒性和聚集。激酶也与不太常见的神经退行性疾病有关，如肌萎缩侧索硬化症（ALS）和脊髓小脑共济失调。尽管靶向激酶具有治疗潜力，但挑战依然存在，包括激酶网络的复杂性、血脑屏障通透性以及缺乏可靠的生物标志物。新兴技术，如共价抑制剂、靶向蛋白降解和联合疗法，为应对这些挑战以及开发更有效的神经退行性疾病治疗方法提供了新途径。
