Differences in Stability, Activity and Mutation Effects Between Human and Mouse Leucine-Rich Repeat Kinase 2.

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in the pathogenesis of Parkinson's disease (PD). Identification of PD-associated LRRK2 mutations has led to the development of novel animal models, primarily in mice. However, the characteristics of human LRRK2 and mouse Lrrk2 protein have not previously been directly compared.

Detection of endogenous S1292 LRRK2 autophosphorylation in mouse tissue as a readout for kinase activity.

Parkinson's disease-linked mutations in enhance the kinase activity of the protein, therefore targeting LRRK2 kinase activity is a promising therapeutic approach. Phosphorylation at S935 of LRRK2 and of its Rab GTPase substrates have proven very useful biomarkers to monitor its kinase activity. Complementary to these approaches autophosphorylation of LRRK2 can be used as a direct kinase activity readout but to date detection of autophosphorylation at endogenous levels in vivo has been limited.

The G2385R risk factor for Parkinson's disease enhances CHIP-dependent intracellular degradation of LRRK2.

Autosomal dominant mutations in () are associated with Parkinson's disease (PD). Most pathogenic mutations result in amino acid substitutions in the central ROC (Ras of complex proteins)-C-terminus of ROC-kinase triple domain and affect enzymatic functions of the protein. However, there are several variants in , including the risk factor G2385R, that affect PD pathogenesis by unknown mechanisms.