Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49 bus 1023, 3000, Leuven, Belgium.
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Neurotherapeutics. 2021 Apr;18(2):949-961. doi: 10.1007/s13311-021-01007-8. Epub 2021 Feb 16.
The development of disease-modifying therapies for Parkinson's disease is a major challenge which would be facilitated by a better understanding of the pathogenesis. Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are key players in Parkinson's disease, but their relationship remains incompletely resolved. Previous studies investigating the effect of LRRK2 on α-synuclein-induced neurotoxicity and neuroinflammation in preclinical Parkinson's disease models have reported conflicting results. Here, we aimed to further explore the functional interaction between α-synuclein and LRRK2 and to evaluate the therapeutic potential of targeting physiological LRRK2 levels. We studied the effects of total LRRK2 protein loss as well as pharmacological LRRK2 kinase inhibition in viral vector-mediated α-synuclein-based Parkinson's disease models developing early- and late-stage neurodegeneration. Surprisingly, total LRRK2 ablation or in-diet treatment with the LRRK2 kinase inhibitor MLi-2 did not significantly modify α-synuclein-induced motor deficits, dopaminergic cell loss, or α-synuclein pathology. Interestingly, we found a significant effect on α-synuclein-induced neuroinflammatory changes in the absence of LRRK2, with a reduced microglial activation and CD4 and CD8 T cell infiltration. This observed lack of protection against α-synuclein-induced toxicity should be well considered in light of the ongoing therapeutic development of LRRK2 kinase inhibitors for idiopathic Parkinson's disease. Future studies will be crucial to understand the link between these neuroinflammatory processes and disease progression as well as the role of α-synuclein and LRRK2 in these pathological events.
帕金森病的疾病修饰疗法的发展是一个重大挑战，如果能更好地了解发病机制，将有助于该疗法的发展。富含亮氨酸重复激酶 2（LRRK2）和α-突触核蛋白是帕金森病的关键因素，但它们之间的关系仍不完全清楚。先前的研究调查了 LRRK2 对临床前帕金森病模型中α-突触核蛋白诱导的神经毒性和神经炎症的影响，但结果相互矛盾。在这里，我们旨在进一步探索α-突触核蛋白和 LRRK2 之间的功能相互作用，并评估针对生理 LRRK2 水平的治疗潜力。我们研究了总 LRRK2 蛋白缺失以及在病毒载体介导的基于α-突触核蛋白的帕金森病模型中，药理学 LRRK2 激酶抑制对早期和晚期神经退行性变的影响。令人惊讶的是，总 LRRK2 缺失或用 LRRK2 激酶抑制剂 MLi-2 进行饮食治疗并没有显著改变α-突触核蛋白诱导的运动缺陷、多巴胺能神经元丧失或α-突触核蛋白病理。有趣的是，我们发现 LRRK2 缺失对α-突触核蛋白诱导的神经炎症变化有显著影响，表现为小胶质细胞激活减少以及 CD4 和 CD8 T 细胞浸润减少。鉴于目前正在为特发性帕金森病开发 LRRK2 激酶抑制剂，因此应该充分考虑到这种对α-突触核蛋白诱导的毒性缺乏保护作用的情况。未来的研究对于理解这些神经炎症过程与疾病进展之间的联系，以及α-突触核蛋白和 LRRK2 在这些病理事件中的作用至关重要。
