Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions

Emma K Theisen; Irma Magaly Rivas-Serna; Peiwen Cheng; Ryan J Lee; Connon I Thomas; Anza Darehshouri; Taylor R Jay; Govind Kunduri; Tasha T Nguyen; Vera Mazurak; M Thomas Clandinin; Thomas R Clandinin; John P Vaughen

doi:10.1016/j.neuron.2026.02.006

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Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions

Journal article

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Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions

Emma K Theisen, Irma Magaly Rivas-Serna, Peiwen Cheng, Ryan J Lee, Connon I Thomas, Anza Darehshouri, Taylor R Jay, Govind Kunduri, Tasha T Nguyen, Vera Mazurak, …

Neuron (Cambridge, Mass.)

03/25/2026

DOI: 10.1016/j.neuron.2026.02.006

PMID: 41887214

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Abstract

The complex morphologies of neurons and glia emerge through profound changes in membrane lipids and proteins during development. Lysosomes are central regulators of membrane remodeling, and mutations that affect lipid turnover in lysosomes are frequently associated with neurological disease. However, how these lysosomal functions might shape brain development remains incompletely understood. By analyzing lipid levels in the Drosophila brain, we discover transient increases in specific sphingolipids during development. This lipid bolus reflects biosynthetic inputs from both neurons and glia, and requires lysosomal catabolism for mature neuronal physiology to emerge. Remarkably, sphingolipid catabolism in glia is substantially driven by the phagolysosomal salvage of neuronal membranes to produce very long-chain ceramide phosphoethanolamine (CPE) lipids. CPE lipids are cell-autonomously required for glial autophagy and ramification into synaptic regions, and a genetic CPE biosensor localizes to infiltrated glial processes. Thus, developmentally regulated lysosomal activity obligately couples neuron-glia metabolic interactions to program dynamic glial morphogenesis.

phagocytosis

lysosomal storage diseases

autophagy

VLCFAs

sphingolipids

very long chain fatty acids

GBA

glia

glucocerebrosidase

arborization

neurodevelopment

LSDs

ceramide phosphoethanolamine

Details

Title: Subtitle: Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions
Creators: Emma K Theisen - Stanford University
Irma Magaly Rivas-Serna - University of Alberta
Peiwen Cheng - University of California, San Francisco
Ryan J Lee - Stanford University
Connon I Thomas - University of Colorado Anschutz Medical Campus
Anza Darehshouri - University of Colorado Anschutz Medical Campus
Taylor R Jay - Oregon Health & Science University
Govind Kunduri - National Cancer Institute
Tasha T Nguyen - Stanford University
Vera Mazurak - University of Alberta
M Thomas Clandinin - University of Alberta
Thomas R Clandinin - Stanford University
John P Vaughen - University of California, San Francisco
Resource Type: Journal article
Publication Details: Neuron (Cambridge, Mass.)
DOI: 10.1016/j.neuron.2026.02.006
PMID: 41887214
NLM abbreviation: Neuron
ISSN: 0896-6273
eISSN: 1097-4199
Publisher: Cell Press
Language: English
Electronic publication date: 03/25/2026
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9985149085602771

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