Journal Article

ER discontinuities are common in C. elegans neurons, revealing a genetically tractable model for ER network maintenance

Mabry, Kelsey N, Keuchel, Brennen, Kushner, Max G, Orgel, Aaron D, Burkewitz, Kristopher, Donahue, Eric K F

2026

Overview

The neuronal endoplasmic reticulum (ER) extends from the soma into axons and dendrites to coordinate protein trafficking, lipid metabolism, inter-organelle organization, and calcium homeostasis. Conserved genes involved in shaping the tubular ER are implicated in neurodevelopment and neurodegeneration, suggesting that ER structure and dynamics influence neuronal health and drive pathogenesis. However, the links between ER morphology and neuronal function and resilience remain incompletely understood. While models typically depict the neuronal ER as a fully continuous network, here we show that micron-scale ER discontinuities in neurites are unexpectedly common in young, unstressed . These discontinuities occur in both axonal and dendritic compartments with a consistent frequency that varies between motor and mechanosensory neuron types. Using live imaging and photokinetic assays of endogenously tagged markers of the ER, we confirm that these gaps reflect true loss of ultrastructural continuity. Subpopulations of ER tubule tips are highly motile, and the majority of ER discontinuities are resolved in less than an hour. Suggesting the formation of discontinuities is linked to cellular damage, their frequency increases with both age and environmental stress. Finally, in agreement with prior observations across models, discontinuities are exacerbated by impairment of certain ER shaping factors involved in hereditary spastic paraplegia, such as reticulon. These findings reveal a model where ER discontinuities are not uncommon in healthy animals, and provide a tractable system in to dissect the molecular mechanisms maintaining ER structural homeostasis in vivo.

• Publisher: Cold Spring Harbor Laboratory Preprints