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LRRK2-NFATc2 Pathway Associated with Neuroinflammation May Be a Potential Therapeutic Target for Parkinson’s Disease
| Content Provider | Scilit |
|---|---|
| Author | Wang, Youcui Zhang, Xiaoqin Chen, Fenghua Chen, Leilei Wang, Jun Xie, Junxia |
| Copyright Year | 2021 |
| Description | 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. |
| Related Links | https://www.dovepress.com/getfile.php?fileID=70580 |
| Ending Page | 2586 |
| Page Count | 4 |
| Starting Page | 2583 |
| ISSN | 11787031 |
| e-ISSN | 11787031 |
| DOI | 10.2147/jir.s301531 |
| Journal | Journal of inflammation research |
| Volume Number | 14 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2021-06-01 |
| Access Restriction | Open |
| Subject Keyword | Neurosciences Parkinson's Disease Neuroinflammation Nfatc2 Α-synuclein |
| Content Type | Text |
| Subject | Immunology and Allergy Immunology |
