Is Inhibition of Kinase Activity the Only Therapeutic Strategy for LRRK2-associated Parkinson's Disease?

Iakov N Rudenko,Ruth Chia,Mark R Cookson

doi:10.1186/preaccept-3356971966272323

Abstract

Is Inhibition of Kinase Activity the Only Therapeutic Strategy for LRRK2-associated Parkinson's Disease?

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