| First Author | Feng L | Year | 2023 |
| Journal | Glia | Volume | 71 |
| Issue | 9 | Pages | 2266-2284 |
| PubMed ID | 37300531 | Mgi Jnum | J:339181 |
| Mgi Id | MGI:7516443 | Doi | 10.1002/glia.24422 |
| Citation | Feng L, et al. (2023) Microglial LRRK2-mediated NFATc1 attenuates alpha-synuclein immunotoxicity in association with CX3CR1-induced migration and the lysosome-initiated degradation. Glia 71(9):2266-2284 |
| abstractText | Synucleinopathies refer to a range of neurodegenerative diseases caused by abnormal alpha-synuclein (alpha-Syn) deposition, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Their pathogenesis is strongly linked to microglial dysfunction and neuroinflammation, which involves the leucine-rich-repeat kinase 2 (LRRK2)-regulated nuclear factor of activated T-cells (NFAT). Of the NFAT family, NFATc1 has been found to be increasingly translocated into the nucleus in alpha-syn stimulation. However, the specific role of NFATc1-mediated intracellular signaling in PD remains elusive in regulating microglial functions. In the current study, we crossbred LRRK2 or NFATc1 conditional knockout mice with Lyz2(Cre) mice to generate mice with microglia-specific deletion of LRRK2 or NFATc1, and by stereotactic injection of fibrillary alpha-Syn, we generated PD models in these mice. We found that LRRK2 deficiency enhanced microglial phagocytosis in the mice after alpha-Syn exposure and that genetic inhibition of NFATc1 markedly diminished phagocytosis and alpha-Syn elimination. We further demonstrated that LRRK2 negatively regulated NFATc1 in alpha-Syn-treated microglia, in which microglial LRRK2-deficiency facilitated NFATc1 nuclear translocation, CX3CR1 upregulation, and microglia migration. Additionally, NFATc1 translocation upregulated the expression of Rab7 and promoted the formation of late lysosomes, resulting in alpha-Syn degradation. In contrast, the microglial NFATc1 deficiency impaired CX3CR1 upregulation and the formation of Rab7-mediated late lysosomes. These findings highlight the critical role of NFATc1 in modulating microglial migration and phagocytosis, in which the LRRK2-NFATc1 signaling pathway regulates the expression of microglial CX3CR1 and endocytic degradative Rab7 to attenuate alpha-synuclein immunotoxicity. |
