LRRK2 and Rab proteins

LRRK2 G2019S and Rab Proteins

LRRK2 is a kinase enzyme and modulates vesicular trafficking by phosphorylating a group of Rab proteins [9]. LRRK2 and Rabs comprise a key response pathway during lysosomal overload stress[3]. The G2019S mutation increases the kinase activity of LRRK2 and results in hyperphosphorylation of proteins Rab8A, Rab10, and Rab12 [8,9]. LRRK2 may also play a role in maintaining the integrity of lysosomes and their homeostasis as mouse neurons expressing the LRRK2 G2019S mutation display altered lysosomal form, including reductions in number and size [8]. Compared to pathogenic mutant forms of LRRK2, VPS35 [D620N] activates Rab10 phosphorylation more potently [9]. 

How VPS35 might regulate LRRK2 and its kinase activity and, hence, Parkinson’s disease, remains unknown [13]. The retromer does not serve as a catalyst, implying there may be an unknown regulator of LRRK2 hyperactivation induced by the VPS35[D620N] mutation. The D620N mutations disrupts lysosomal function, which may lead to LRRK2 recruitment to the lysosome and heightened phosphorylation [10].