Pharmacological inhibition of the NLRP3 inflammasome prevents synuclein pathology and dopaminergic degeneration in Parkinson's disease
Richard Gordon1, Eduardo A. Albornoz1, Daniel C. Christie1, Monica R. Langley4, Vinod Kumar1, Susanna Manotovani1 , Avril A. B. Robertson1, Mark S. Butler1, Dominic B. Rowe6, Luke A. O'Neill7, Anumantha G. Kanthasamy4, Kate Schroder1, Matthew A. Cooper1,*, Trent M. Woodruff1,* 1The University of Queensland, Australia; 4Dept. of Biomedical Sciences, Iowa State University, USA; 6Department of Neurology, Macquarie University, Australia; 7Trinity College Dublin, Ireland *firstname.lastname@example.org and/or email@example.com
Fibrillar synuclein is implicated in cell-to-cell transmission and neuronal degeneration in Lewy body diseases, but mechanisms linking synuclein pathology and dopaminergic neuronal loss to chronic microglial neuroinflammation have not been defined. We show that activation of the microglial NLRP3 inflammasome is a common pathway triggered by both fibrillar synuclein and dopaminergic degeneration in the absence of synuclein aggregates. Cleaved caspase-1 and the inflammasome adapter protein ASC are elevated in the substantia nigra of PD patients, and in multiple preclinical PD models including 6-hydroxydopamine, MitoPark, and the preformed fibril model of synuclein pathology.
NLRP3 activation by fibrillar synuclein in microglia results in a delayed, but robust activation of the NLRP3 inflammasome, with substantial extracellular ASC release in the absence of pyroptosis. Nanomolar doses of the potent small molecule NLRP3 inhibitor, MCC950, abolished fibrillar synuclein-mediated NLRP3 activation and extracellular ASC release. Further, MCC950 is active in the central nervous system following oral dosing, and can mitigate inflammasome activation, motor deficits and nigrostriatal dopaminergic degeneration. Crucially, chronic NLRP3 inhibition with MCC950 effectively blocks fibrillar synuclein mediated motor deficits, dopamine loss and pathological synuclein spread in vivo. These findings suggest that the microglial NLRP3 inflammasome may be a sustained source of neuroinflammation that drives progressive neuropathology in PD, and highlights NLRP3 as a druggable, disease-modifying therapeutic target for PD.
References C. Dempsey et al., Brain, Behavior, and Immunity, 2017, 61, 306-316. R.C. Coll, et al. Nature Medicine, 2015, 21, 248-255 Funding This work was supported by Michael J Fox Foundation Grant 12626
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