Journal Article

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

Grotemeyer, Alexander, Blum, Robert, Koprich, James B., Brotchie, Jonathan M., Volkmann, Jens, Ip, Chi Wang, Fischer, Judith F.

2023

Overview

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. Graphical Abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: alpha-Synuclein - metabolism / Animals / Antibodies / Biomedical and Life Sciences / Biomedicine / CD4 antigen / CD8 antigen / Cell death / Disease Models, Animal / Dopamine receptors / Dopaminergic cells / Dopaminergic Neurons / Humans / Immunology / Inflammasome / Inflammasomes / Inflammasomes - metabolism / Laboratories / Lymphocytes / Lymphocytes T / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / Microglia - metabolism / Movement disorder / Movement disorders / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neuroinflammation / Neuroinflammatory Diseases / Neurology / Neuroprotection / Neurosciences / 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)