LRRK2 inhibitors and their potential in the treatment of Parkinson's disease: current perspectives

Abstract

Major advances in understanding how genetics underlies Parkinson's disease (PD) have provided new opportunities for understanding disease pathogenesis and potential new targets for therapeutic intervention. One such target is leucine-rich repeat kinase 2 (LRRK2), an enigmatic enzyme implicated in both familial and idiopathic PD risk. Both academia and industry have promoted the development of potent and selective inhibitors of LRRK2, and these are currently being employed to assess the safety and efficacy of such compounds in preclinical models of PD. This review examines the evidence that LRRK2 kinase activity contributes to the pathogenesis of PD and outlines recent progress on inhibitor development and early results from preclinical safety and efficacy testing. This review also looks at some of the challenges remaining for translation of LRRK2 inhibitors to the clinic, if indeed this is ultimately warranted. As a disease with no current cure that is increasing in prevalence in line with an aging population, there is much need for developing new treatments for PD, and targeting LRRK2 is currently a promising option.

Keywords: Rab; autophagy; inflammation; inhibitor; lysosome; synuclein.

Figure 1

Pathogenic LRRK2 mutations increase LRRK2 autophosphorylation and downstream substrate phosphorylation. Notes: The most common pathogenic LRRK2 missense mutations are located in the catalytic kinase domain or the ROC-COR tandem GTPase domain. All mutations increase the low levels of autophosphorylation on LRRK2, particularly Ser1292, and all mutations increase the phosphorylation of downstream Rab GTPase substrates such as Rab10. Abbreviation: LRRK2, leucine-rich repeat kinase 2.

Figure 2

Peripheral actions of LRRK2 inhibitors. Notes: LRRK2 has a particularly high expression in kidney, lung, spleen, and peripheral immune cells. A number of studies using knockout, kinase inactive knockin, and LRRK2 inhibitor-treated rodents have reported potential peripheral side effects of LRRK2 manipulation. To what extent these relate to a safety liability in humans is still unknown; however, compared to many drugs, LRRK2 inhibitors appear to be well tolerated. Abbreviations: LRRK2, leucine-rich repeat kinase 2; WBC, white blood cells; RBC, red blood cells.

Figure 3

Potential mediators of LRRK2 pathobiology. Notes: LRRK2 has been implicated in a variety of biological processes known to be perturbed in Parkinson’s disease. Rab GTPases, a number of which were recently identified as LRRK2 substrates, also contribute to the complex regulation of many PD-implicated biological processes. Abbreviations: LRRK2, leucine-rich repeat kinase 2; PD, Parkinson’s disease.

Figure 4

Measuring LRRK2 inhibitor target engagement. Notes: LRRK2 inhibitors cause the loss of constitutive phosphorylation on serine residues 910 and 935. However, these are not autophosphorylation sites and only serve as indirect measures of target engagement. Unlike S910 and S935, S1292 is a bona fide LRRK2 autophosphorylation site, but its low stoichiometry of phosphorylation makes it difficult to measure. LRRK2 can also directly phosphorylate certain Rab GTPase proteins such as Rab10, and these may serve as good direct measures of target engagement if robust assays can be developed. Abbreviation: LRRK2, leucine-rich repeat kinase 2.