Introduction: Pathogenic mutations in leucine-rich repeat protein kinase-2 (LRRK2), particularly G2019S, constitute the most common cause of autosomal dominant PD. Methods: Mouse models encoding human mutant alpha-synuclein (SNCA A53T) and LRRK2 G2019S were treated with a brain-penetrant kinase inhibitor (BK40196). Behavior, nigrostriatal and mesolimbic dopamine (DA) pathways were examined. Results: Mice harboring LRRK2 G2019S do not show age-dependent motor symptoms, but mice encoding SNCA A53T display motor deficits, while both strains exhibit anxiety-like behavior and BK40196 improves motor and behavioral defects. BK40196, a multi-kinase inhibitor of Abelson (Abl), Discoidin domain receptor (DDR)-1, c-KIT and FYN, alters microglial morphology and alpha-synuclein levels in SNCA A53T mice and improves DA neurotransmission, primarily via the nigrostriatal system. BK40196 inhibits brain LRRK2 G2019S (IC50 of 89nM) and does not affect phosphorylated or total peripheral LRRK2 levels (lungs, kidneys, liver, etc.). LRRK2 G2019S mice treated with BK40196 exhibit distinct increases in DA in mesolimbic neurons such as the nucleus accumbens (NAcc), suggesting differential mechanisms of DA neurotransmission in mutant alpha-synuclein and LRRK2 models of PD. Conclusions: LRRK2 G2019S may primarily involve mesolimbic pathways leading to nonmotor symptoms independent of the motor and behavioral manifestations associated with alpha-synuclein via the nigrostriatal system. BK40196 may provide a comprehensive and synergistic therapeutic approach that addresses multiple mechanisms to reduce the pathologies related to LRRK2 G2019S and/or SNCA in PD. The multiple pathologies of PD necessitate a holistic approach that simultaneously targets inflammation and autophagy and LRRK2 inhibition.
Liu et al. (Sat,) studied this question.