Karami Mahsa, Sanaye Pantea Majma, Ghorbani Atousa, Amirian Roshanak, Goleij Pouya, Babamohamadi Mehregan, Izadi Zhila
Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
J Transl Med. 2025 Jul 8;23(1):754. doi: 10.1186/s12967-025-06354-0.
Parkinson's disease (PD) is a neurodegenerative disease with severe movement problems. Current treatments mainly focus on symptom management by reducing dopaminergic pathways in the brain. Despite these therapies, ongoing disease progression undermines the effectiveness of prevalent approaches, necessitating exploring alternative methods anchored on genetic factors, notably the leucine-rich repeat kinase 2 (LRRK2) gene. Exploring LRRK2 gene pathogenesis has highlighted various mechanisms that may contribute to treating PD, including protein accumulation, altered cytoskeletal dynamics, neuro-inflammation, autophagy, and mitochondrial dysfunction. Based on the findings, there is an actual correlation between elevated levels of LRRK2 and the biomarkers and assays of PD. Furthermore, research results have suggested inhibiting LRRK2 as a therapeutic intervention targeting pathogenic mechanisms with varying degrees of efficacy. Our review wants to understand how LRRK2 works in the body and its relationship with the occurrence of PD by providing biochemical evidence, LRRK2 gene mutations and pathology, and the role of this gene in the immune system. We also discuss targeted therapies such as kinase inhibitors and Proteolysis targeting chimera and the application of using the LRRK2 protein to diagnose PD and develop bioassay designs. Finally, we mention the clinical trials conducted and the challenges and safety required.
帕金森病（PD）是一种伴有严重运动问题的神经退行性疾病。目前的治疗主要集中在通过减少大脑中的多巴胺能通路来管理症状。尽管有这些疗法，但疾病的持续进展削弱了现有方法的有效性，因此有必要探索基于遗传因素的替代方法，特别是富含亮氨酸重复激酶2（LRRK2）基因。对LRRK2基因发病机制的探索突出了各种可能有助于治疗帕金森病的机制，包括蛋白质积累、细胞骨架动力学改变、神经炎症、自噬和线粒体功能障碍。基于这些发现，LRRK2水平升高与帕金森病的生物标志物和检测方法之间存在实际关联。此外，研究结果表明抑制LRRK2作为一种针对致病机制的治疗干预措施具有不同程度的疗效。我们的综述旨在通过提供生化证据、LRRK2基因突变与病理学以及该基因在免疫系统中的作用，来了解LRRK2在体内的作用及其与帕金森病发生的关系。我们还讨论了激酶抑制剂和靶向嵌合体蛋白水解等靶向疗法，以及使用LRRK2蛋白诊断帕金森病和开发生物检测设计的应用。最后，我们提到了已进行的临床试验以及所需面对的挑战和安全性问题。
