Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are known today as the most common genetic cause of Parkinson’s disease (PD). LRRK2 is a large protein that is hypothesized to regulate other proteins as a scaffold in downstream signaling pathways. This is supported by the multiple domain composition of LRRK2 with several protein-protein interaction domains combined with kinase and GTPase activity. LRRK2 is highly phosphorylated at sites that are strictly controlled by upstream regulators, including its own kinase domain. In cultured cells, most pathogenic mutants display increased autophosphorylation at S1292, but decreased phosphorylation at sites controlled by other kinases. We only begin to understand how LRRK2 phosphorylation is regulated and how this impacts its physiological and pathological function. Intriguingly, LRRK2 kinase inhibition, currently one of the most prevailing disease-modifying therapeutic strategies for PD, induces LRRK2 dephosphorylation at sites that are also dephosphorylated in pathogenic variants. In addition, LRRK2 kinase inhibition can induce LRRK2 protein degradation, which might be related to the observed inhibitor-induced adverse effects on the lung in rodents and non-human primates, as it resembles the lung pathology in LRRK2 knock-out animals. In this review, we will provide an overview of how LRRK2 phosphorylation is regulated and how this complex regulation relates to several molecular and cellular features of LRRK2.

今天，编码富含亮氨酸的重复激酶2（LRRK2）的基因突变是帕金森氏病（PD）的最常见遗传原因。LRRK2是一种大蛋白，被认为可以调节其他蛋白作为下游信号传导途径的支架。LRRK2的多个结构域组成与几个蛋白-蛋白相互作用结构域结合了激酶和GTPase活性，为这一点提供了支持。LRRK2在受上游调节剂（包括其自身的激酶结构域）严格控制的位点被高度磷酸化。在培养的细胞中，大多数致病突变体在S1292处显示出增加的自磷酸化作用，但在其他激酶控制的位点处的磷酸化作用降低。我们仅开始了解LRRK2磷酸化是如何调控的，以及如何影响其生理和病理功能。有趣的是 LRRK2激酶抑制目前是PD中最流行的疾病修饰治疗策略之一，它会在致病变体中也去磷酸化的位点诱导LRRK2去磷酸化。此外，LRRK2激酶抑制作用可诱导LRRK2蛋白降解，这可能与在啮齿动物和非人类灵长类动物中观察到的抑制剂诱导的对肺的不利影响有关，因为它类似于LRRK2基因敲除动物的肺部病理。在这篇综述中，我们将概述LRRK2磷酸化的调控方式，以及这种复杂的调控与LRRK2的几种分子和细胞特征之间的关系。LRRK2激酶抑制可诱导LRRK2蛋白降解，这可能与在啮齿动物和非人类灵长类动物中观察到的抑制剂诱导的对肺的不良反应有关，因为它类似于LRRK2敲除动物的肺部病理。在这篇综述中，我们将概述LRRK2磷酸化的调控方式，以及这种复杂的调控与LRRK2的几种分子和细胞特征之间的关系。LRRK2激酶抑制可诱导LRRK2蛋白降解，这可能与在啮齿动物和非人类灵长类动物中观察到的抑制剂诱导的对肺的不良反应有关，因为它类似于LRRK2敲除动物的肺部病理。在这篇综述中，我们将概述LRRK2磷酸化的调控方式，以及这种复杂的调控与LRRK2的几种分子和细胞特征之间的关系。