Tripartite Crosstalk between Cytokine IL-1/I, NMDA-R and Misplaced Mitochondrial Anchor in Neuronal Dendrites Is a Novel Pathway for Neurodegeneration in Inflammatory Diseases

The mitochondrial anchor syntaphilin (SNPH) is a key mitochondrial protein normally expressed in axons to maintain neuronal health by positioning mitochondria along axons for metabolic needs. However, in 2019 we discovered a novel form of excitotoxicity that results when SNPH is misplaced into neuronal dendrites in disease models. A key unanswered question about this SNPH excito-toxicity is the pathologic molecules that trigger misplacement or intrusion of SNPH into dendrites. Here, we identified two different classes of pathologic molecules that interact to trigger dendritic SNPH intrusion. Using primary hippocampal neuronal cultures from mice of either sex, we demonstrated that the pro-inflammatory cytokine IL-1/I interacts with NMDA to trigger SNPH intrusion into dendrites. First, IL-1/I and NMDA each individually triggers dendritic SNPH intrusion. Second, IL-1/I and NMDA do not act inde-pendently but interact. Thus, blocking NMDAR by the antagonist MK-801 blocks IL-1/I from triggering dendritic SNPH intrusion. Further, decoupling the known interaction between IL-1/I and NMDAR by tyrosine inhibitors prevents either IL-1/I or NMDA from triggering dendritic SNPH intrusion. Third, neuronal toxicity caused by IL-1/I or NMDA is strongly ameliorated in SNPH-/- neurons. Together, we hypothesize that the known bipartite IL-1/I/NMDAR crosstalk converges to trigger misplacement of SNPH in dendrites as a final common pathway to cause neurodegeneration. Targeting dendritic SNPH in this novel tripartite IL-1/I/NMDAR/SNPH inter-action could be a strategic downstream locus for ameliorating neurotoxicity in inflammatory diseases.

Automated summary

The interaction between pro-inflammatory cytokine IL-1/I and NMDA triggers the misplacement of mitochondrial anchor protein SNPH into neuronal dendrites, leading to excitotoxicity. Blocking the interaction between IL-1/I and NMDAR can prevent the intrusion of SNPH into dendrites. Neuronal toxicity caused by IL-1/I or NMDA is significantly reduced in SNPH-/- neurons. Targeting dendritic SNPH in the tripartite IL-1/I/NMDAR/SNPH interaction could be a strategic approach to ameliorate neurotoxicity in inflammatory diseases.