PMC

Schematic representation of LRRK2 and the pathogenic mutations associated with PD ARM, Armadillo; ANK, Ankyrin repeat; LRR, leucine-rich repeat; ROC, Ras of complex proteins: GTPase; COR, C-terminal of ROC; WD40, WD-40 domain. Potential pathogenic mutations are shown together.

The possible pathogenic mechanism links LRRK2 and Parkinson’s disease α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction and autophagy-lysosomal system all take part in the pathogenic of PD. Open and filled arrows show positive (activating) and negative (suppressing) interactions, respectively.

LRRK2-mediated the phosphorylation of tubulin-associated tau LRRK2 interacts with tubulin-associated tau, resulting in the formation of a tripartite complex. The interaction between LRRK2 and β-tubulin is mediated by the LRRK2 Roc domain and β-tubulin C termini. Tubulin-associated tau was phosphorylated by LRRK2. LRRK2 interacted directly with GSK-3β, and that His–GSK-3β bound to the kinase domain of LRRK2 (thick line). Phosphorylation of tau by GSK-3β was stimulated by LRRK2 (thin arrow). P.G2019S-LRRK2 had higher binding affinity for GSK-3β and showed much stronger stimulatory activity (thick line and arrow).