Boehringer Ingelheim Pharma GmbH & Co KG, CNS Research, Biberach an der Riss, Germany.
PLoS One. 2010 Oct 7;5(10):e13191. doi: 10.1371/journal.pone.0013191.
Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, however, the underlying pathogenic mechanisms are poorly understood. Several in vitro studies have shown that the most frequent mutation, LRRK2(G2019S), increases kinase activity and impairs neuronal survival. LRRK2 has been linked to the mitogen-activated protein kinase kinase kinase family and the receptor-interacting protein kinases based on sequence similarity within the kinase domain and in vitro substrate phosphorylation.
METHODOLOGY/PRINCIPAL FINDINGS: We used an unbiased proteomic approach to identify the kinase signaling pathways wherein LRRK2 may be active. By incubation of protein microarrays containing 260 signal transduction proteins we detected four arrayed Ste20 serine/threonine kinase family members (TAOK3, STK3, STK24, STK25) as novel LRRK2 substrates and LRRK2 interacting proteins, respectively. Moreover, we found that protein kinase C (PKC) zeta binds and phosphorylates LRRK2 both in vitro and in vivo.
CONCLUSIONS/SIGNIFICANCE: Ste20 kinases and PKC zeta contribute to neuronal Tau phosphorylation, neurite outgrowth and synaptic plasticity under physiological conditions. Our data suggest that these kinases may also be involved in synaptic dysfunction and neurite fragmentation in transgenic mice and in human PD patients carrying toxic gain-of-function LRRK2 mutations.
富含亮氨酸重复激酶 2（LRRK2）中的显性突变是帕金森病最常见的遗传原因，但潜在的发病机制尚不清楚。几项体外研究表明，最常见的突变 LRRK2(G2019S) 会增加激酶活性并损害神经元存活。基于激酶结构域内的序列相似性和体外底物磷酸化，LRRK2 与丝裂原活化蛋白激酶激酶激酶家族和受体相互作用蛋白激酶有关。
方法/主要发现：我们使用无偏蛋白质组学方法来鉴定 LRRK2 可能活跃的激酶信号通路。通过孵育含有 260 种信号转导蛋白的蛋白质微阵列，我们分别检测到四个排列的 Ste20 丝氨酸/苏氨酸激酶家族成员（TAOK3、STK3、STK24、STK25）作为 LRRK2 的新型底物和相互作用蛋白。此外，我们发现蛋白激酶 C（PKC）zeta 在体内和体外均与 LRRK2 结合并磷酸化。
结论/意义：Ste20 激酶和 PKC zeta 在生理条件下有助于神经元 Tau 磷酸化、轴突生长和突触可塑性。我们的数据表明，这些激酶也可能参与转染小鼠中的突触功能障碍和轴突碎裂以及携带毒性获得功能 LRRK2 突变的人类 PD 患者。
