LRRK2-NFATc2 Pathway Associated with Neuroinflammation May Be a Potential Therapeutic Target for Parkinson's Disease
Youcui Wang1,2,3, Xiaoqin Zhang1,2,3, Fenghua Chen1,2,3
1Institute of Brain Science and Disease, Qingdao University, Qingdao, People's Republic of China.
Abstract:
Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). However, the molecular mechanisms involved in extracellular α‑synuclein-induced proinflammatory microglial responses through Toll-like receptor 2 (TLR2) are unclear. Leucine-rich repeat kinase 2 (LRRK2) is a serine/threonine kinase, and its mutations are closely related to autosomal dominant PD. Recently, Masliah et al characterized a novel-specific neuroinflammation cascade dependent on LRRK2-NFATc2 in microglia activated by neuron-released α-synuclein. LRRK2 selectively phosphorylated and induced nuclear translocation of NFATc2 to activate a neuroinflammation cascade. In this cascade, LRRK2 kinase was activated by neuron-released α-synuclein in microglia via TLR2. Further, NFATc2, as a kinase substrate for LRRK2, was directly phosphorylated, which accelerated nuclear translocation of NFATc2, where cytokine/chemokine gene expression including TNF-α and IL-6 is regulated by NFATc2 transcriptional activity, resulting in a neurotoxic inflammatory environment. Moreover, an abnormal increase of NFATc2 in nuclear was observed in the brains of patients and a mouse model of PD. Additionally, the administration of an LRRK2 inhibitor could ameliorate neuroinflammation, prevent neuronal loss, and improve motor function. Therefore, modulation of LRKK2-NFATc2 signaling cascade might be a potential therapeutic target for the treatment of PD.
Insights
Leucine-rich repeat kinase 2 (LRRK2) signaling in microglia drives neuroinflammation in Parkinson's disease via Toll-like receptor 2 (TLR2). Inhibiting LRRK2 reduces inflammation and neuronal loss, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Neuroinflammation is a key factor in Parkinson's disease (PD) pathogenesis.
- The precise mechanisms linking extracellular alpha-synuclein to microglial activation via Toll-like receptor 2 (TLR2) remain incompletely understood.
- Mutations in Leucine-rich repeat kinase 2 (LRRK2) are a significant cause of autosomal dominant PD.
Purpose of the Study:
- To elucidate the molecular mechanisms of neuroinflammation in Parkinson's disease.
- To investigate the role of LRRK2-NFATc2 signaling in microglial activation by alpha-synuclein.
- To identify potential therapeutic targets for PD treatment.
Main Methods:
- Characterization of a novel neuroinflammation cascade involving LRRK2 and NFATc2 in microglia.
- Analysis of LRRK2 activation by neuron-released alpha-synuclein via TLR2.
- Assessment of NFATc2 phosphorylation and nuclear translocation.
- Measurement of cytokine/chemokine gene expression (TNF-α, IL-6).
- Examination of NFATc2 levels in human PD brains and a PD mouse model.
- Evaluation of LRRK2 inhibitor efficacy in a PD mouse model.
Main Results:
- Neuron-released alpha-synuclein activates LRRK2 in microglia through TLR2.
- LRRK2 directly phosphorylates NFATc2, promoting its nuclear translocation.
- NFATc2 transcriptional activity drives the expression of pro-inflammatory cytokines like TNF-α and IL-6.
- Elevated nuclear NFATc2 levels were observed in PD patients and a PD mouse model.
- LRRK2 inhibition ameliorated neuroinflammation, prevented neuronal loss, and improved motor function in a PD mouse model.
Conclusions:
- The LRRK2-NFATc2 signaling pathway is crucial for alpha-synuclein-induced neuroinflammation in Parkinson's disease.
- Targeting the LRRK2-NFATc2 cascade represents a promising therapeutic strategy for PD.
- Modulating LRRK2 kinase activity may offer a novel approach to treating Parkinson's disease.
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