LRRK2 links genetic and sporadic Parkinson's disease

Abstract

The past two decades in research has revealed the importance of leucine-rich repeat kinase 2 (LRRK2) in both monogenic and sporadic forms of Parkinson's disease (PD). In families, mutations in LRRK2 can cause PD with age-dependent but variable penetrance and genome-wide association studies have found variants of the gene that are risk factors for sporadic PD. Functional studies have suggested that the common mechanism that links all disease-associated variants is that they increase LRRK2 kinase activity, albeit in different ways. Here, we will discuss the roles of LRRK2 in areas of inflammation and vesicular trafficking in the context of monogenic and sporadic PD. We will also provide a hypothetical model that links inflammation and vesicular trafficking together in an effort to outline how these pathways might interact and eventually lead to neuronal cell death. We will also highlight the translational potential of LRRK2-specific kinase inhibitors for the treatment of PD.

Keywords: Parkinson's disease; genome-wide association studies; leucine-rich repeat kinase.

Figure 1.. Physiological pathways of LRRK2 activity.

A common function of LRRK2 in genetic and sPD can be modeled on physiological signaling pathways important for neuronal survival. A generic apoptotic neuron (without dendrites for simplicity) and reactive glial cells are depicted and highlighted pathways are shown along with downstream effects of increased LRRK2 activity. Blue arrows indicate a gain-of-function pathway where increased LRRK2 kinase activity may drive dysfunction while green arrows highlight the molecular events of pharmacological LRRK2 inhibition. (A) LRRK2 has been linked to autophagosome maturation and impaired phagocytosis nominating these processes as possible culprits in the clearance of aggregated synuclein. (B) LRRK2 is activated in systems of induced inflammation while higher LRRK2 levels are seen in immune cells from idiopathic PD patients compared with healthy controls. Accumulation of extracellular synuclein can further induce an inflammatory response and this, in turn, can lead to LRRK2 activation. (C) LRRK2 interacts with Rab29 and mediates TGN dynamics while Rab29 expression can drive LRRK2 activation. Active LRRK2 phosphorylates Rab GTPases with downstream effects on vesicular trafficking as well as impaired autophagy/lysosomal pathways (D) that can impair clearance of aggregated proteins. (E) Progressive increase in ROS with ageing can activate LRRK2 that in turn can affect mitochondrial function and impair mitochondrial clearance through mitophagy.