02.06.2025
Neurons with large arbors are often more vulnerable to neurodegenerative processes. Using Drosophila as a model for neurodegenerative disorders, we show that inflammatory cytokine signaling induced by the integrated stress response is a key determinant of axon length–dependent vulnerability to synapse loss. Neuron-derived inflammatory signals activate glia which preferentially target the synaptic domains of neurons with the longest axons. Our findings suggest that an evolutionarily conserved pathway contributes to neuronal vulnerability during early phases of neurodegenerative disorders including Parkinson’s disease, Amyotrophic lateral sclerosis, hereditary spastic paraplegia, and spinocerebellar ataxia in which synapse loss leads to decline of neuronal function.
Tenedini FM, Yin C, Huang J, Dhiman N, Soba P*, Parrish JZ* (2025). Axon length-dependent synapse loss is mediated by neuronal cytokine-induced glial phagocytosis. PNAS, 122 (21) e2422752122. doi.org/10.1073/pnas.2422752122.