Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

Iakov N Rudenko,Mark R Cookson,Ruth Chia

doi:10.1186/1741-7015-10-20

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.

Highlights

Parkinson’s disease (PD) is a relatively common agerelated neurodegenerative disorder [1]
We have discussed some therapeutic intervention points for leucine-rich repeat kinase 2 (LRRK2) PD based on what is currently known about LRRK2 function and LRRK2-induced cytotoxicity
LRRK2 has been implicated in many cellular pathways, including apoptosis, cytoskeleton dynamics, protein translation and other cell signaling cascades, current data are predominantly descriptive and do not explain much of the underlying molecular mechanisms

Summary

Introduction

Parkinson’s disease (PD) is a relatively common agerelated neurodegenerative disorder [1]. Application of kinase inhibitors to cells expressing LRRK2 causes loss of phosphorylation at S910 and S935, located at the N terminus of LRR This is further associated with the loss of binding to 14-3-3 protein and rearrangement of LRRK2 into filamentous structures. Blocking the GTP-binding pocket of ROC or stimulation of GTPase activity to limit a pathogenic interaction could be a potential therapeutic target for LRRK2-associated PD [14]. These might be helpful for R1441- and Y1699-mutant LRRK2, but to date no such tools are available that could achieve this goal.

Conclusion

14. Cookson MR