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bioRxiv · 10.1101/2024.02.19.580982

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

Ko, H.·Dawson, T. M.·Seo, B. A.·Kwon, S.-H.·Kim, D.·Kim, H.-B.·Ma, S.-X.·Gadhave, K.·Burgess, N.·Mao, X.·Rosenthal, L. S.·Redding-Ochoa, J.·Troncoso, J. C.·Lee, S.·Dawson, V. L.
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Abstract

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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/580982v2_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@10c010aorg.highwire.dtl.DTLVardef@1183b23org.highwire.dtl.DTLVardef@1d289dborg.highwire.dtl.DTLVardef@158b6ef_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.

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Ko, H., Dawson, T. M., Seo, B. A., Kwon, S.-H., Kim, D., Kim, H.-B., Ma, S.-X., Gadhave, K., Burgess, N., Mao, X., Rosenthal, L. S., Redding-Ochoa, J., Troncoso, J. C., Lee, S., Dawson, V. L.. 2024-02-25. Pathologic α-Synuclein-NOD2 Interaction and RIPK2 Activation Drives Microglia-Induced Neuroinflammation in Parkinson's Disease. https://doi.org/10.1101/2024.02.19.580982

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