Human leucine-rich repeat kinase 1 and 2: intersecting or unrelated functions?

Mutations in LRRK2 (leucine-rich repeat kinase 2) are associated with both familial and sporadic PD (Parkinson's disease). LRRK1 (leucine-rich repeat kinase 1) shares a similar domain structure with LRRK2, but it is not linked to PD. LRRK proteins belong to a gene family known as ROCO, which codes for large proteins with several domains. All ROCO proteins have a ROC (Ras of complex proteins) GTPase domain followed by a domain of unknown function [COR (C-terminal of ROC)]. LRRK2, LRRK1 and other ROCO proteins also possess a kinase domain. To date, the function of LRRK1 and both the physiological and the pathological roles of LRRK2 are only beginning to unfold. The comparative analysis of these two proteins is a strategy to single out the specific properties of LRRKs to understand their cellular physiology. This comparison is the starting point to unravel the pathways that may lead to PD and eventually to develop therapeutic strategies for its treatment. In the present review, we discuss recently published results on LRRK2 and its paralogue LRRK1 concerning their evolutionary significance, biochemical properties and potential functional roles.