LRRK2

LRRK2, short for leucine-rich repeat kinase 2, is a gene that encodes a large cytoplasmic serine/threonine kinase. The protein belongs to the ROCO family and contains multiple domains, including armadillo repeats, ankyrin repeats, leucine-rich repeats, a ROC GTPase domain, a COR domain, and a kinase domain. It participates in vesicular trafficking, autophagy, and mitochondrial dynamics, in part through phosphorylation of Rab GTPases such as Rab8A and Rab10.

Genetic significance and disease association. Pathogenic variants in LRRK2 are a major genetic contributor to Parkinson’s disease (PD), causing autosomal dominant familial PD and increasing risk for sporadic PD. The best-characterized mutation is G2019S, which increases kinase activity. Other disease-associated variants include R1441C/G/H, Y1699C, and I2020T. Penetrance is age-dependent and influenced by genetic and environmental factors; allele frequencies vary by ethnicity, with higher prevalence in certain populations such as Ashkenazi Jewish and some North African groups.

Pathogenic mechanisms. Many disease-linked variants elevate LRRK2 kinase activity or disrupt its GTPase function, leading to abnormal phosphorylation of Rab substrates and disturbances in endolysosomal pathways, autophagy, and mitochondrial homeostasis. These alterations are thought to contribute to neurodegeneration in PD.

Clinical implications and research. LRRK2 is a target for therapeutic development in PD. LRRK2 inhibitors have entered clinical trials to reduce pathogenic kinase activity, with biomarker strategies (for example, measuring Rab10 phosphorylation) and exploratory imaging approaches under development. Safety considerations from preclinical studies have emphasized monitoring lung and other tissues during chronic inhibition.

Beyond PD, LRRK2 variants have been linked to other conditions, including Crohn’s disease and susceptibility to certain infections, reflecting broader roles in immune function. Expression is widespread, with notable presence in brain and immune cells.