L'RRK de Triomphe: A solution for LRRK2 GTPase activity?

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a central protein in the pathogenesis of Parkinson's disease (PD), yet its normal function has proved stubbornly hard to elucidate. Even though it remains unclear how pathogenic mutations affect LRRK2 to cause PD, recent findings provide increasing cause for optimism. We summarise here the developing consensus over the effect of pathogenic mutations in the Ras of complex proteins and C-terminal of Roc domains on LRRK2 GTPase activity. This body of work has been greatly reinforced by our own study of the protective R1398H variant contained within the LRRK2 GTPase domain. Collectively, data point towards the pathogenicity of GTP-bound LRRK2 and strengthen a working model for LRRK2 GTPase function as a GTPase activated by dimerisation. Together with the identification of the protective R1398H variant as a valuable control for pathogenic mutations, we have no doubt that these triumphs for the LRRK2 field will accelerate research towards resolving LRRK2 function and towards new treatments for PD.