Redirecting microglia phenotype via inhibition of NFAT1 ameliorates deficits in mouse model of synucleinopathies.

The abnormal deposition of α-synuclein (α-syn) and neuroinflammation are key features of synucleinopathies. We recently demonstrated that leucine-rich repeat kinase 2 (LRRK2) and nuclear factor of activated T cells 1 (NFAT1) modulate the neurotoxic inflammation in synucleinopathies mediated by microglia. Therefore, we hypothesized that targeting NFAT1 might ameliorate the microglial neurotoxicity in synucleinopathies. Here we utilized 11R-VIVIT, an NFAT1 inhibitory peptide, in in vivo, ex vivo and in vitro synucleinopathy models to evaluate the effects of NFAT1 inhibition to test this hypothesis. The microglia in synucleinopathy mouse models become excessively activated due to chronic disease conditions, thereby increasing the expressions of proinflammatory cytokines in these cells and decreasing the expressions of genes associated with microglial mobility and phagocytosis, strongly associated with neurodegeneration and pathogenic α-syn deposition. However, we observed that the inhibition of NFAT1 decreased the microglial neuroinflammation, thereby ameliorating neurodegeneration and α-syn neuropathology in vivo. Furthermore, the comprehensive in vivo transcriptomic analysis of the microglia revealed that the inhibition of NFAT1 restored their mobility and phagocytic abilities via upregulations of related genes. Our study proposes that the inhibition of NFAT1 redirects the excessively activated microglia to active healthy microglia, thereby reducing synucleinopathy neurotoxicity.