Identification of axon length-dependent gene expression programs

Many neurodegenerative disorders (NDDs) preferentially affect neurons with long or complex axonal arbors. However, our understanding of this specific vulnerability is limited. We hypothesize that axon length represents a molecularly definable source of vulnerability common to many NDDs, and indeed we found that Drosophila neurons with long axons are intrinsically more vulnerable to degeneration than same-type neurons with short axons. In preliminary studies we have defined molecular markers whose expression covaries with axon length and have developed a robust platform for single cell transcriptomics, in vivo analysis of axon length-dependent effects on synaptic connectivity, and behavioral diagnostics of length-dependent axon degeneration. We will leverage the significant advantages of this system to systematically identify genes whose levels covary with axon length and assay functions for these genes in length-dependent axon degeneration. Altogether, our studies will provide fundamental insight into mechanisms of axon length-dependency in degeneration, addressing a fundamental gap in our understanding of NDDs. Project Number: 1R21NS149049-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: JAY PARRISH | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $427,625 | Activity Code: R21 | Study Section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354376