The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

• DOI: 10.1002/glia.23728
• Publication Date: 2019-10-09T13:41:27Z
• Authors: Vandana Deora; John D. Lee; Eduardo A. Albornoz; Luke McAlary; Cyril J. Jagaraj; Avril A. B. Rober...; Julie D. Atkin; Matthew A. Cooper; Kate Schroder; Justin J. Yerbury; Richard Gordon; Trent M. Woodruff
• Keywords: 0301 basic medicine; 572; glia; Inflammasomes; Amyotrophic Lateral Sclerosis; 2804 Cellular and Molecular Neuroscience; 610; Mice, Transgenic; Disease Models, Animal; 03 medical and health sciences; Superoxide Dismutase-1; IL-1β; 2808 Neurology; NLR Family, Pyrin Domain-Containing 3 Protein; Medicine and Health Sciences; motor neuron disease; Disease Progression; Animals; Humans; Microglia; innate immunity

Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such β-amyloid and α-synuclein trigger microglial activation, leading caspase-1 IL-1β secretion. Both contribute disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting role for NLRP3. Prior studies, however, suggested mice microglia do not express NLRP3, generated independent Here, we demonstrate using Nlrp3-GFP gene knock-in that mice. We show both aggregated soluble activates primary cleavage, ASC speck formation, secretion dose- time-dependent manner. Importantly, was unable induce from deficient Nlrp3, or pretreated with specific inhibitor MCC950, confirming complex mediating SOD1-induced upregulation also observed TDP-43Q331K ALS model, TDP-43 wild-type mutant proteins could activate inflammasomes NLRP3-dependent Mechanistically, identified generation reactive oxygen species ATP events required -mediated activation. Taken together, our data pathological inflammasome. inhibition may therefore be potential therapeutic approach arrest progression.