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.