Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia

Tenedini FM, Yin C, Huang JM, Dhiman N, Soba P, Parrish JZ (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 122

Article Number: e2422752122

Journal Issue: 21

DOI: 10.1073/pnas.2422752122

Abstract

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors but the cellular and molecular bases for neurite length-dependent vulnerability of neurons to degeneration is largely unknown. Using Drosophila sensory neurons as a model system we show that neuronal activation of the integrated stress response triggers expression of the Interleukin-6 homolog unpaired 3 (upd3), which is both necessary and sufficient for axon length–dependent degeneration of presynapses. Upd3 activates phagocytic glia, triggering phagocytic removal of presynapses preferentially on neurons with long axons, thus revealing an intrinsic axon length–dependent vulnerability to glial insult. Finally, we found that axon length–dependent presynapse loss in fly models of human NDDs utilized this pathway, requiring upd3 and glial expression of the phagocytic receptor draper. Our studies identify inflammatory cytokine signaling and glial phagocytosis as key determinants of axon length–dependent vulnerability, thus mechanistically linking these hallmarks of NDDs.

Authors with CRIS profile

Neena Dhiman Professur für Zelluläre und Molekulare Neurophysiologie (Heisenberg-Professur) Peter Soba Professur für Zelluläre und Molekulare Neurophysiologie (Heisenberg-Professur)

Involved external institutions

University of Washington US United States (USA) (US)

How to cite

APA:

Tenedini, F.M., Yin, C., Huang, J.M., Dhiman, N., Soba, P., & Parrish, J.Z. (2025). Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia. Proceedings of the National Academy of Sciences of the United States of America, 122(21). https://doi.org/10.1073/pnas.2422752122

MLA:

Tenedini, Federico Marcello, et al. "Inflammatory cytokine upd3 induces axon length–dependent synapse removal by glia." Proceedings of the National Academy of Sciences of the United States of America 122.21 (2025).

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