LRRK2

LRRK2

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 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.

References:

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).

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