Pathological aggregation of -Synuclein (-Syn) and neuroinflammation are closely linked to Parkinsons disease (PD). However, the specific regulators of the neuroinflammation caused by pathological -syn remain obscure. In this study, we show that NOD2/RIPK2 signaling is a crucial regulator of neuroinflammation in PD. Pathological -syn binds to NOD2, causing self-oligomerization and complex formation with RIPK2, leading to RIPK2 ubiquitination and activation of MAPK and NF-kB. Notably, this NOD2/RIPK2 signaling is particularly active in microglia of human PD brains and the -Syn preformed fibril (-Syn PFF) mouse model. Depleting NOD2 or RIPK2 reduces neuroinflammation and protects against dopamine neuron degeneration in a pathologic -Syn mouse model by blocking the formation of neurotoxic reactive astrocytes caused by microglia activation. The discovery of NOD2/RIPK2 signaling as a key regulator of neuroinflammation in PD provides a new understanding of -Syn-driven neuroinflammation and neurodegeneration in PD and a potential new therapeutic strategy.
Graphical Abstract
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org.highwire.dtl.DTLVardef@53c89eorg.highwire.dtl.DTLVardef@9812c7org.highwire.dtl.DTLVardef@1f8f962org.highwire.dtl.DTLVardef@bcc955_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefPathological -Synuclein (-Syn) binds to the microglial NOD2 protein, which in turn triggers NOD2/RIPK2 complex and RIPK2 phosphorylation/ubiquitination. This process activates the NF-kB/MAPK pathways, ultimately leading to neurotoxic reactive astrocyte-induced dopaminergic neurodegeneration. Depletion of RIPK2 (RIPK2 KO) or NOD2 (NOD2) protects dopamine neurons in a mouse model of Parkinsons disease (PD). These findings provide insights into -Syn-driven neuroinflammation and offer potential therapeutic strategies for PD.
HighlightsNOD2/RIPK2 signaling is identified as a crucial regulator of neuroinflammation in PD.
NOD2/RIPK2 signaling is highly active in microglia in human PD brains and -Syn PFF mouse models.
Pathological -Syn binds to NOD2, triggering self-oligomerization and RIPK2 complex formation, leading to MAPK and NF-kB activation
Genetic depletion of NOD2 or RIPK2 reduces neuroinflammation and protects dopamine neurons by blocking the formation of neurotoxic reactive astrocytes.
