Abstract
Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, β-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease. Furthermore, BHB can readily cross the blood brain barrier suggesting that it could have therapeutic benefits for the management of PD. In this study, we evaluated if BHB could inhibit chronic microglial inflammasome activation induced by pathological fibrillar synuclein aggregates. Interestingly, we found that BHB treatment almost completely blocked all aspects of inflammasome activation and pyroptosis induced by ATP and monosodium urate (MSU) crystals, consistent with previously published reports in macrophages. Surprisingly however, BHB did not inhibit inflammasome activation and release of IL-1β or caspase-1 induced by synuclein fibrils. Our results demonstrate that BHB does not block the upstream pathways regulating inflammasome activation by synuclein fibrils and suggest that synuclein mediated inflammasome activation proceeds via distinct mechanisms compared to traditional NLRP3 activators such as ATP and MSU.
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RG conceived the project, designed experiments and supervised the study. VD and EA performed experiments and data analysis with assistance from KZ and RG. RG and VD wrote the manuscript. All authors edited and approved the final version of the manuscript.
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Deora, V., Albornoz, E.A., Zhu, K. et al. The Ketone Body β-Hydroxybutyrate Does Not Inhibit Synuclein Mediated Inflammasome Activation in Microglia. J Neuroimmune Pharmacol 12, 568–574 (2017). https://doi.org/10.1007/s11481-017-9754-5
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DOI: https://doi.org/10.1007/s11481-017-9754-5