Identifying mechanisms of axon length-dependent degeneration

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors. However, our understanding of this specific vulnerability is limited. Using Drosophila melanogaster as a model system, we identified a genetic pathway regulating neuronal production of the proinflammatory cytokine upd3, an Interleukin-6 orthologue, which drives axon length-dependent presynapse removal by glial cells. Remarkably, ectopic upd3 expression induces axon length- dependent presynapse loss in wild-type neurons, demonstrating that long axons and their connections are intrinsically vulnerable to removal. Our central hypothesis, based on extensive preliminary data analyzing axon length-dependent synaptic phenotypes at the structural, functional and behavioral level is that axon length-dependent degeneration is driven by neuronal stress-induced inflammatory cytokine production and subsequent activation of microglia-like phagocytes that recognize signals produced in a length-dependent fashion on target axons. We rigorously test this hypothesis, defining the features of the upd3 signaling system, identifying and characterizing the phagocytic glia, and defining intrinsic signals underlying the vulnerability of long axons to degeneration. Altogether, our studies will provide fundamental insight into a mechanisms of axon length-dependency in degeneration, addressing a fundamental gap in our understanding of NDDs. Project Number: 1R01NS143223-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: JAY PARRISH (+1 co-PI) | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $502,070 | Activity Code: R01 | Study Section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11294825