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Their pathogenesis is strongly linked to microglial dysfunction and neuroinflammation, which involves the leucine\u2010rich\u2010repeat kinase 2 (LRRK2)\u2010regulated nuclear factor of activated T\u2010cells (NFAT). Of the NFAT family, NFATc1 has been found to be increasingly translocated into the nucleus in \u03b1\u2010syn stimulation. However, the specific role of NFATc1\u2010mediated intracellular signaling in PD remains elusive in regulating microglial functions. In the current study, we crossbred LRRK2 or NFATc1 conditional knockout mice with <jats:italic>Lyz2<\/jats:italic><jats:sup><jats:italic>Cre<\/jats:italic><\/jats:sup> mice to generate mice with microglia\u2010specific deletion of LRRK2 or NFATc1, and by stereotactic injection of fibrillary \u03b1\u2010Syn, we generated PD models in these mice. We found that LRRK2 deficiency enhanced microglial phagocytosis in the mice after \u03b1\u2010Syn exposure and that genetic inhibition of NFATc1 markedly diminished phagocytosis and \u03b1\u2010Syn elimination. We further demonstrated that LRRK2 negatively regulated NFATc1 in \u03b1\u2010Syn\u2010treated microglia, in which microglial LRRK2\u2010deficiency 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 \u03b1\u2010Syn degradation. In contrast, the microglial NFATc1 deficiency impaired CX3CR1 upregulation and the formation of Rab7\u2010mediated late lysosomes. These findings highlight the critical role of NFATc1 in modulating microglial migration and phagocytosis, in which the LRRK2\u2010NFATc1 signaling pathway regulates the expression of microglial CX3CR1 and endocytic degradative Rab7 to attenuate \u03b1\u2010synuclein immunotoxicity.<\/jats:p>","DOI":"10.1002\/glia.24422","type":"journal-article","created":{"date-parts":[[2023,6,10]],"date-time":"2023-06-10T13:43:50Z","timestamp":1686404630000},"page":"2266-2284","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Microglial <scp>LRRK2<\/scp>\u2010mediated <scp>NFATc1<\/scp> attenuates \u03b1\u2010synuclein immunotoxicity in association with <scp>CX3CR1<\/scp>\u2010induced migration and the lysosome\u2010initiated degradation"],"prefix":"10.1002","volume":"71","author":[{"given":"Linjuan","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Neurology Center for Cognitive Neurology, Fujian Medical 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