Leucine-rich repeat kinase 2 (LRRK2) G2019S mutant (LRRK2 G2019S)

Leucine-rich repeat kinase 2 (LRRK2) is a large, multi-domain protein that functions as both a GTPase and a serine/threonine-protein kinase (UniProt Q5S007). The G2019S mutation, located within the kinase domain's activation loop, is the most prevalent genetic cause of Parkinson's disease, contributing to both familial and sporadic cases (PMID: 15514145). This mutation induces a gain-of-function by significantly increasing the enzyme's catalytic activity, which leads to the hyperphosphorylation of Rab GTPase substrates like Rab10 (PMID: 26824392). Such aberrant signaling disrupts essential cellular processes, including vesicular trafficking, lysosomal homeostasis, and autophagy, which are critical for maintaining neuronal health (PMID: 30639476). Consequently, the LRRK2 G2019S mutant kinase domain is a high-priority therapeutic target, with several small-molecule inhibitors currently in clinical development (PMID: 32029618). These drugs aim to restore normal cellular function by potently and selectively inhibiting the mutant kinase activity, although monitoring for potential pulmonary and renal side effects remains a key challenge in clinical translation (PMID: 25459545).

Other names

DardarinPARK8RIPK7ROCO2Leucine-rich repeat serine/threonine-protein kinase 2

Kinase inhibition (ATP-competitive inhibition)