Summary Pathological aggregation of α-Synuclein (α-Syn) and neuroinflammation are closely linked to Parkinson’s disease (PD). However, the specific regulators of the neuroinflammation caused by pathological α-syn remain obscure. In this study, we show that NOD2/RIPK2 signaling is a crucial regulator of neuroinflammation in PD. Pathological α-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 α-Syn preformed fibril (α-Syn PFF) mouse model. Depleting NOD2 or RIPK2 reduces neuroinflammation and protects against dopamine neuron degeneration in a pathologic α-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 α-Syn-driven neuroinflammation and neurodegeneration in PD and a potential new therapeutic strategy. Graphical Abstract In brief Pathological α-Synuclein (α-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 Parkinson’s disease (PD). These findings provide insights into α-Syn-driven neuroinflammation and offer potential therapeutic strategies for PD. Highlights NOD2/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 α-Syn PFF mouse models. Pathological α-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.

Pathologic α-Synuclein-NOD2 Interaction and RIPK2 Activation Drives Microglia-Induced Neuroinflammation in Parkinson’s Disease