TY - JOUR T1 - Tripartite Crosstalk between Cytokine IL-1β, NMDA-R and Misplaced Mitochondrial Anchor in Neuronal Dendrites Is a Novel Pathway for Neurodegeneration in Inflammatory Diseases JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7318 LP - 7329 DO - 10.1523/JNEUROSCI.0865-22.2022 VL - 42 IS - 38 AU - Dinesh C. Joshi AU - Chuan-Li Zhang AU - Deepali Mathur AU - Alex Li AU - Gaurav Kaushik AU - Zu-Hang Sheng AU - Shing-Yan Chiu Y1 - 2022/09/21 UR - http://www.jneurosci.org/content/42/38/7318.abstract N2 - 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 excitotoxicity 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-1β interacts with NMDA to trigger SNPH intrusion into dendrites. First, IL-1β and NMDA each individually triggers dendritic SNPH intrusion. Second, IL-1β and NMDA do not act independently but interact. Thus, blocking NMDAR by the antagonist MK-801 blocks IL-1β from triggering dendritic SNPH intrusion. Further, decoupling the known interaction between IL-1β and NMDAR by tyrosine inhibitors prevents either IL-1β or NMDA from triggering dendritic SNPH intrusion. Third, neuronal toxicity caused by IL-1β or NMDA is strongly ameliorated in SNPH−/− neurons. Together, we hypothesize that the known bipartite IL-1β/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-1β/NMDAR/SNPH interaction could be a strategic downstream locus for ameliorating neurotoxicity in inflammatory diseases.SIGNIFICANCE STATEMENT SNPH is a key mitochondrial protein normally expressed specifically in healthy axons to help position mitochondria along axons to match metabolic needs. In 2019 we discovered that misplacement of SNPH into neuronal dendrites causes a novel form of excitotoxicity in rodent models of multiple sclerosis. A key unanswered question about this new form of dendritic SNPH toxicity concerns pathologic molecules that trigger toxic misplacement of SNPH into dendrites. Here, we identified two major categories of pathologic molecules, the pro-inflammatory cytokines and NMDA, that interact and converge to trigger toxic misplacement of SNPH into dendrites. We propose that a dendritic mitochondrial anchor provides a novel, single common target for ameliorating diverse inflammatory and excitatory injuries in neurodegenerative diseases. ER -