Laboratory for Biomolecular Modelling, Katholieke Universiteit Leuven, Belgium.
CNS Neurol Disord Drug Targets. 2011 Sep 1;10(6):724-40. doi: 10.2174/187152711797247858.
Intense research efforts are currently directed at elucidating the etiology of Parkinson's disease (PD). One approach that has begun to shed light on the PD pathogenic pathways is the identification of disease genes through genetic linkage or association studies. These studies have revealed that several kinases may be involved in PD, as some PD genes encode kinases themselves while other PD genes are found in the same cellular pathways as kinases. Two of these kinases stand out as potential drug targets for novel PD therapy, namely leucine rich repeat kinase 2 (LRRK2) and the alpha-synuclein (α-syn) phosphorylating polo-like kinase 2 (PLK2). Indeed, both α- syn and LRRK2 show genetic linkage as well as genetic association with PD, indicating their relevance to a large number of PD cases. Also, due to the dominant mode of α-syn and LRRK2 inheritance and based on current knowledge of LRRK2 and α-syn phosphorylation by PLK2, inhibition of LRRK2 and PLK2 may constitute a potential therapy for PD. Here we discuss the function of these kinases as well as progress in their validation as drug targets for the treatment of PD.
目前，人们正在进行深入的研究，以阐明帕金森病（PD）的病因。一种方法是通过遗传连锁或关联研究来鉴定疾病基因，这已经开始揭示 PD 的致病途径。这些研究表明，几种激酶可能与 PD 有关，因为一些 PD 基因本身编码激酶，而其他 PD 基因则存在于与激酶相同的细胞途径中。其中两种激酶作为新型 PD 治疗的潜在药物靶点脱颖而出，即富含亮氨酸重复激酶 2（LRRK2）和α-突触核蛋白（α-syn）磷酸化 Polo 样激酶 2（PLK2）。事实上，α-syn 和 LRRK2 都显示出与 PD 的遗传连锁和遗传关联，表明它们与大量 PD 病例有关。此外，由于 α-syn 和 LRRK2 的显性遗传模式，以及基于目前对 PLK2 磷酸化 LRRK2 和 α-syn 的了解，抑制 LRRK2 和 PLK2 可能构成 PD 的潜在治疗方法。在这里，我们讨论了这些激酶的功能以及将它们验证为治疗 PD 的药物靶点的进展。
