ASC specks exacerbate αsynuclein pathology via amplifying NLRP3 inflammasome activities.
J Neuroinflammation
; 20(1): 26, 2023 Feb 05.
Article
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| MEDLINE
| ID: mdl-36740674
ABSTRACT
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 α-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 αsynuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated αsynuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal αsynuclein aggregation.CONCLUSIONS:
In conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated αsynuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
/
Inflamasomas
Idioma:
En
Revista:
J Neuroinflammation
Asunto de la revista:
NEUROLOGIA
Año:
2023
Tipo del documento:
Article