ASC specks exacerbate α-synuclein pathology via amplifying NLRP3 inflammasome activities

Background Inflammasome activation has a pathogenic role in Parkinson's disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established.Methods Herein, we used human A53T mutant alpha-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection.Results We observed a direct relationship between levels of ASC protein and misfolded alpha-synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by alpha-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated alpha-synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal alpha-synuclein aggregation.Conclusions In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated alpha-synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.

Automated summary

Inflammasome activation plays a pathogenic role in Parkinson's disease (PD). The up-regulation of the inflammasome adaptor ASC and the formation of ASC specks have been observed in PD brains and models. However, the contribution of ASC specks in propagating inflammasome activation and pathological progression in PD is not fully understood.