Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin, is an enzyme that in humans is encoded by the PARK8 gene. LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease and also Crohn's disease.
An overview of LRRK2
Leucine-rich repeat kinase 2 (LRRK2), a large multi-domain protein belonging to the Roco protein family, is associated with Parkinson’s disease. The major functional domains includes LRRK2 specific repeats, leucine rich repeat (LRR), Ras of complex proteins, C-terminal of Roc, WD40 and the protein kinase domain. The protein kinase domain is a member of tyrosine-like serine/threonine kinase subfamily, and is similar to Pho-interacting protein kinase. Thus, it is speculated that LRRK2 has the activity of GTP enzyme and protein kinase, and can be used as scaffold protein to provide a platform for the aggregation of multiprotein signal complexes. The analysis of subcellular localization showed that LRRK2 is mainly distributed in endoplasmic reticulum, golgi apparatus and terminal synaptic terminals.
Inhibition of LRRK2
LRRK2 is a hot target for the study of Parkinson’s disease due to its indispensable function. Early studies on LRRK2 kinase inhibitors have identified a number of active compounds by screening existing kinase inhibitors. However, these LRRK2 inhibitors obtained by this screening method have serious off-target effect. In 2011, LRRK2-IN-1 was discovered as a LRRK2 inhibitor with high efficiency and selectivity, promoting the development of new structures of LRRK2 inhibitors. Hatcher et al reported that a LRRK2 inhibitor JH-Ⅱ-127 with good central activity is a dose-dependent inhibitorthat regulates the phosphorylation and dephosphorylation of Ser910 and Ser935. Experiments in vivo showed that LDN-22684 developed by Liu group is a reversible, time-dependent and non-competitive inhibitor, only exerting its function at the ATP binding site. Currently, LRRK2 inhibitors are still in the pre-clinical research stage, and the toxicity and stability of some highly evaluated inhibitors are being studied for clinical use.
LRRK2 and diseases
So far, there are over thirty disease-associated variants in the LRRK2 gene. Accumulating evidences suggest that LRRK2 gene is closely associated with Parkinson’s disease, and there is an autosomal domain mutation (the G2019S mutation) in the LRRK2 gene located in the protein kinase domain. It is widely believed that the different mutations in genes could probably lead to different diseases. For instance, the Y1699C mutation is reported to cause dementia and amyotrophy.
1. Gandhi, P. N., Chen, S. G. & Wilsondelfosse, A. L. Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson's disease. Journal of Neuroscience Research 87, 1283-1295 (2010).
2. Cookson, M. R. LRRK2 Pathways Leading to Neurodegeneration. Current Neurology & Neuroscience Reports 15, 42 (2015).
3. Price, A., Manzoni, C., Cookson, M. R. & Lewis, P. A. The LRRK2 signalling system. Cell & Tissue Research, 1-12 (2018).
4. West, A. B. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Experimental Neurology 298 (2017).