LRRK2 in Parkinson’s disease: biochemical functions

Abstract

Leucine‐rich repeat kinase 2 (LRRK2) is a large, complex, multidomain protein containing kinase and GTPase enzymatic activities and multiple protein–protein interaction domains. Mutations linked to autosomal dominant forms of Parkinson’s disease result in amino acid changes throughout the protein and alterations in both its enzymatic properties and interactions. The best characterized mutation to date, G2019S, leads to increased kinase activity, and mutations in the GTPase domain, such as R1441C and R1441G, have also been reported to influence kinase activity. Therefore, an examination of LRRK2’s properties as a kinase is important for understanding the mechanisms underlying the disorder and has the potential to lead to therapeutics. These findings also suggest that there may be complex interplay between the functional domains of LRRK2. Here, we review LRRK2’s biochemical functions based on structural and kinetic studies of the enzymatic domains, its potential substrates and the role of its interactions. Despite the field’s embryonic understanding of the true relevance of these substrates and interactions, initial studies are providing clues with respect to its pathophysiological functions. Together, these findings should increase our understanding of mechanisms underlying Parkinson’s disease and place LRRK2 as a unique molecular target for effective therapeutic development.

A QUICK Screen for Lrrk2 Interaction Partners – Leucine-rich Repeat Kinase 2 is Involved in Actin Cytoskeleton Dynamics

“…Because Lrrk2 is a multi-domain protein, comprising in addition to its GTPase and kinase activity several protein interaction domains that are likely to facilitate various PPIs, different biochemical functions can be accomplished by Lrrk2. This view is supported by several studies demonstrating that Lrrk2 is involved in various, not necessarily independent, physiological processes including kinase signaling, vesicular transport, regulation of microtubules, cytoskeleton assembly and the chaperone system (78). The proteomic approach taken here renders new insights on how Lrrk2 molecularly interacts with the cytoskeletal machinery controlling actin turnover.…”

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

“…Recently, a series of excellent reviews on LRRK2 was published in FEBS J. (104)(105)(106)(107)(108). I suggest referring to these reviews for more detailed information.…”

Receptor-interacting protein (RIP) kinase family

“…G2019S mutation results in the increased kinase activity, whereas R1441C/G mutations cause defective GTPase activity and also influence kinase activity. 72 Moreover, all the variants of RIP7 and their contribution to Parkinson's disease have been recently examined and summarized by Paisan-Ruiz. 73 The kinase activity, GTP-binding (GTPase) and WD40 domain of RIP7 are all reported to be implicated in RIP7's neurotoxicity.…”