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

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.

Figure 1

Schematic representation of potential therapeutic strategies for LRRK2-associated Parkinson's disease. This diagram highlights some therapeutic possibilities for leucine-rich repeat kinase 2 (LRRK2)-induced cytotoxicity, taking into account how different mutations cause different protein biochemical alterations, recruitment of mediators of cytotoxicity or loss of interaction with regulatory proteins such as 14-3-3. LRRK2 is represented as a simplified linear dimer with the enzymatic ROC-COR-kinase domains, and protein-protein interaction domains, N-terminal ankyrin, LRR, leucine-rich repeat and WD40. Locations of LRRK2 pathogenic mutations are also shown (N1437H, R1441C/G, Y1699C, G2019S and I2020T). Broadly, the possible therapeutic points of intervention for LRRK2 are through (A) inhibition of kinase activity and GTP binding, (B) disruption of LRRK2 dimerization, (C) interference with the protein-protein interaction platform and (D) preservation of constitutive phosphorylation of LRRK2. Detailed discussion of these approaches can be found in the main text under Therapeutic strategies for LRRK2-associated Parkinson's disease.