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Metabolic Labeling of Leucine Rich Repeat Kinases 1 and 2 with Radioactive Phosphate
Published on: September 18, 2013
Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration
Zach Dwyer1, Chris Rudyk1, Ashley Thompson1
1Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
Abstract:
Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease and many inflammatory processes. Thus, we assessed the role of LRRK2 in the context of endotoxin (lipopolysaccharide, LPS)-induced inflammation of the substantia nigra together with the environmental toxicant, paraquat, that has been implicated in PD. Here we found that LRRK2 ablation prevented the loss of dopaminergic neurons and behavioral deficits (motor) induced by LPS priming followed by paraquat exposure. The LRRK2 ablation also provoked a phenotypic shift in LPS-primed microglia cells. The LRRK2 deficiency reduced their "activated" morphology and upregulation of the inflammatory phagocytic regulator, WAVE2 (critical for actin remodeling), while the chemokine receptor, CX3CR1, was elevated in isolated CD11b+ myeloid cells. Furthermore, LRRK2 knockout attenuated the signs of oxidative stress and morphological changes induced in primary microglia by LPS treatment. However, induced WAVE2 expression together with LPS exposure in microglia overcame the inhibitory effects of LRRK2 knockout, suggesting WAVE2 may be acting downstream of LRRK2. Neither WAVE2 nor did LRRK2 knockout influence LPS-induced cytokine elevations in the microglia. We are the first to show the importance of LRRK2 in neurodegenerative and inflammatory processes in this multi-hit toxin model of PD. These data are consistent with the proposition that LRRK2 and WAVE2 are useful therapeutic targets for PD or other conditions with a prominent neuroinflammatory component.
Insights
Leucine-rich repeat kinase 2 (LRRK2) deficiency protected against Parkinson's disease-like neurodegeneration and motor deficits. LRRK2 ablation altered microglial responses to inflammation, suggesting LRRK2 and WAVE2 as potential therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Leucine-rich repeat kinase 2 (LRRK2) is implicated in Parkinson's disease (PD) and inflammatory conditions.
- Environmental toxins like paraquat and endotoxins (lipopolysaccharide, LPS) contribute to neuroinflammation and PD pathogenesis.
Purpose of the Study:
- To investigate the role of LRRK2 in a multi-hit toxin model of Parkinson's disease.
- To determine how LRRK2 deficiency affects neuroinflammation and dopaminergic neuron survival.
Main Methods:
- Utilized a mouse model with LRRK2 gene knockout (ablation).
- Administered LPS priming followed by paraquat exposure to induce Parkinson's disease-like pathology.
- Analyzed dopaminergic neuron loss, motor behavior, microglial morphology, and molecular markers (WAVE2, CX3CR1).
Main Results:
- LRRK2 ablation prevented dopaminergic neuron loss and motor deficits induced by LPS and paraquat.
- LRRK2 deficiency altered microglia phenotype, reducing activation and WAVE2 expression while increasing CX3CR1.
- LRRK2 knockout attenuated oxidative stress and morphological changes in LPS-treated microglia, though WAVE2 induction could override these effects.
Conclusions:
- LRRK2 plays a critical role in neuroinflammation and neurodegeneration in this PD model.
- LRRK2 and WAVE2 represent potential therapeutic targets for Parkinson's disease and other neuroinflammatory disorders.
