Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson's disease

• Published in: Journal of neuroinflammation 2023-03, Vol.20 (1), p.79-79, Article 79
• Main Authors: Grotemeyer, Alexander, Fischer, Judith F, Koprich, James B, Brotchie, Jonathan M, Blum, Robert, Volkmann, Jens, Ip, Chi Wang
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Antibodies; CD4 antigen; CD8 antigen; Cell death; Disease Models, Animal; Dopamine receptors; Dopaminergic cells; Dopaminergic Neurons; Humans; Inflammasome; Inflammasomes; Inflammasomes - metabolism; Laboratories; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Microglia - metabolism; Movement disorder; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neuroinflammation; Neuroinflammatory Diseases; Neuroprotection; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson's disease; Pathology; Pyrin protein; Substantia nigra; Sulfonamides - pharmacology; Synuclein; Vectors (Biology)
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02759-0

Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson's disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4 and CD8 T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.