Fig. 3

LRRK2-PINK1 kinase pair balance in modulation of TH-DA pathway, significant to PD pathogenesis and therapy. LRRK2 and PINK1 form a functional kinase pair balance to regulate TH expression and DA production in DA neurons. a LRRK2 enhances TH expression and DA synthesis, while PINK1 inhibits TH expression and DA production. LRRK2 and PINK1 can promote proteasome degradation of each other, leading to a function l kinase balance in steady state. Under physiological conditions, the moderate DA level in brains will cause mild stress to DA neurons by reactive ROS, DAQs and DOPAL generated from DA oxidation and MAO catalyzed DA metabolism. DA neurons can survive and be healthy. b However when LRRK2 is mutated, LRRK2 kinase activity can be increased to up-regulate TH and DA levels. The increased LRRK2 kinase activity will also promote PINK1 degradation to inhibit PINK1 function. This will lead to an imbalance between LRRK2 and PINK1 kinase pair, contributing to increased TH and DA levels, elevated generation of toxic DA by-products and DA neuron vulnerability. c Vice versa, under PINK1 mutations, the PINK1 kinase activity can be impaired, which will also disturb the LRRK2-PINK1 kinase balance, leading to deregulated TH-DA pathway, enhanced generation of toxic DA by-products, and DA neuron vulnerability