Journal
MOLECULAR NEURODEGENERATION
Volume 11, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s13024-016-0094-3
Keywords
microRNA-7; NLRP3 inflammasome; alpha-Synuclein; Neuroinflammation; Parkinson's disease
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Funding
- National Natural Science Foundation of China [81473196, 81573403, 81473195, 81202514]
- Natural Science Foundation of Jiangsu Province [BK20130039]
- key project of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province [15KJA310002]
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Background: alpha-Synuclein (alpha-Syn), a pathological hallmark of Parkinson's disease (PD), has been recognized to induce the production of interleukin-1 beta in a process that depends, at least in vitro, on nod-like receptor protein 3 (NLRP3) inflammasome in monocytes. However, the role of NLRP3 inflammasome activation in the onset of PD has not yet been fully established. Results: In this study, we showed that NLRP3 inflammasomes were activated in the serum of PD patients and the midbrain of PD model mice. We further clarified that alpha-syn activated the NLRP3 inflammasome through microglial endocytosis and subsequent lysosomal cathepsin B release. Deficiency of caspase-1, an important component of NLRP3 inflammasome, significantly inhibited alpha-syn-induced microglia activation and interleukin-1 beta production, which in turn alleviated the reduction of mesencephalic dopaminergic neurons treated by microglia medium. Specifically, we demonstrated for the first time that Nlrp3 is a target gene of microRNA-7 (miR-7). Transfection of miR-7 inhibited microglial NLRP3 inflammasome activation whereas anti-miR-7 aggravated inflammasome activation in vitro. Notably, stereotactical injection of miR-7 mimics into mouse striatum attenuated dopaminergic neuron degeneration accompanied by the amelioration of microglial activation in MPTP-induced PD model mice. Conclusions: Our study provides a direct link between miR-7 and NLRP3 inflammasome-mediated neuroinflammation in the pathogenesis of PD. These findings will give us an insight into the potential of miR-7 and NLRP3 inflammasome in terms of opening up novel therapeutic avenues for PD.
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