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

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. ### Competing Interest Statement The authors have declared no competing interest.