Synergistic Effects of Multi-Kinase Inhibition on LRRK2-G2019S and Alpha-Synuclein Pathologies in Models of
Xiaoguang Liu1, Sean Baxely1, Michaeline L Hebron1
1Translational Neurotherapeutics Program, Laboratory for Dementia and Parkinsonism, Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA.
Abstract:
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.
Insights
A novel brain-penetrant kinase inhibitor, BK40196, improved motor and behavioral deficits in mouse models of Parkinson's disease (PD). This drug targets LRRK2 G2019S and alpha-synuclein pathologies, offering a potential synergistic therapeutic approach for PD.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Leucine-rich repeat protein kinase-2 (LRRK2) G2019S mutations are a common cause of autosomal dominant Parkinson's disease (PD).
- Alpha-synuclein (SNCA) mutations, like A53T, are also implicated in PD pathogenesis.
- Understanding the distinct pathways affected by LRRK2 and SNCA is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the therapeutic potential of a brain-penetrant kinase inhibitor (BK40196) in mouse models of PD.
- To examine the effects of BK40196 on motor function, behavior, and dopamine pathways in LRRK2 G2019S and SNCA A53T models.
- To elucidate the differential roles of LRRK2 and SNCA in PD pathogenesis and their response to kinase inhibition.
Main Methods:
- Treatment of mouse models with LRRK2 G2019S and SNCA A53T mutations using the brain-penetrant kinase inhibitor BK40196.
- Assessment of behavioral phenotypes, including motor deficits and anxiety-like behavior.
- Analysis of nigrostriatal and mesolimbic dopamine pathways, microglial morphology, and alpha-synuclein levels.
Main Results:
- BK40196 significantly improved motor and behavioral defects in both LRRK2 G2019S and SNCA A53T mouse models.
- The inhibitor altered microglial morphology and reduced alpha-synuclein levels in SNCA A53T mice, enhancing dopamine neurotransmission.
- BK40196 selectively inhibited brain LRRK2 G2019S, increasing dopamine in mesolimbic pathways, suggesting distinct therapeutic mechanisms for LRRK2 and SNCA pathologies.
Conclusions:
- LRRK2 G2019S may primarily affect non-motor symptoms via mesolimbic pathways, distinct from alpha-synuclein's nigrostriatal involvement in motor deficits.
- BK40196 demonstrates potential as a synergistic therapeutic agent for PD by addressing multiple pathological mechanisms.
- A holistic approach targeting inflammation, autophagy, and LRRK2 inhibition is necessary for comprehensive PD treatment.
Related Concept Videos
01:24Parkinson Disease ll: Pathophysiology
01:24Parkinson Disease l: Introduction
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:15Parkinson's Disease: Overview
01:37Neural Regulation
01:22Lysosomal Hydrolases